Melanocortin receptor ligands

The present invention relates to peptides that are melanocortin-4 (MC4-R) receptor ligands, pharmaceutically acceptable salts thereof, methods of using such peptides for treating mammals, and useful pharmaceutical compositions containing such peptides.

[0002] Melanocortins are a family of regulatory peptides that are formed as a result of post-translational processing of proopiomelanocortin prohormone (POMC; 131 amino acids in length). POMC is processed into three classes of hormones; melanocortins, adrenocorticotropic hormone and various endorphins (e.g. lipotropin) (Cone, et al., Recent Prog. Horm. Res., 51: 287-317, (1996); Cone et al., Ann. NY Acad. Sci., 31: 342-363, (1993)).

[0003] Melanocortins have been found in a wide variety of normal human tissues, including the brain, adrenals, skin, testicles, spleen, kidney, ovary, lung, thyroid, liver, colon, small intestine and pancreas (Tatro, JB et al., Endocrinol. 121) : 1900-1907 (1987); Mountjoy, KG et al., Science 257: 1248-1251 (1992); Chhajlani, V. et al., FEBS Lett. 309: 417-420 (1992); Gantz, I. and in. J. Biol. Chem. 268: 8246-8250 (1993) and Gantz, I. et al., J. Biol. Chem. 268: 15174-15179 (1993)).

[0004] Melanocortin peptides have been found to have a variety of physiological activities, including behavioral and memory control, influencing neurotrophic and antipyretic properties, as well as influencing the modulation of the immune system. In addition to the well-known effects on adrenocorticotropic hormone (adrenocorticotropic hormone, ACTH) and melanocytes (melanocyte stimulating hormone, MSH), melanocortins have also been shown to control the cardiovascular system, analgesia, thermoregulation, and release of other neurohumoral factors, including prolactin, hormone luteinizing and biogenic amines (De Wied, D. et al., Methods Achiev. Exp. Pathol. 15: 167-199 (1991); De Wied, D. et al., Physiol. Rev. 62: 977-1059 (1982 ); Guber, KA et al., Am. J. Physiol. 257: R681-R694 (1989); Walker JM et al., Science 210: 1247-1249 (1980); Murphy, MT et al., Science 221: 192-193 (1983); Ellerkmann, E. et al., Endocrinol. 130: 133-138 (1992) and Versteeg, DHG et al., Life Sci. 38: 835-840 (1986)).

[0005] Melanocortin binding sites have also been found to be distributed in a wide variety of tissue types, including tear and submandibular glands, pancreas, adipose tissue, bladder, duodenum, spleen, brain and gonadal tissues, as well as malignant melanomas. To date, five melanocortin receptors (MC-Rs) have been characterized. These include the melanocyte-specific receptor (MC1-R), the ACTH-specific adrenocortical receptor (MC2-R), the melanocortin 3 receptor (MC3-R), the melanocortin 4 receptor (MC4-R) and the melanocortin 5 receptor (MC5-R) . All melanocortin receptors bind to melanocyte stimulating hormones (MHCs) belonging to the class of peptide hormones (Cone, RD et al., Ann. NY Acad. Sci., 680: 342-363 (1993); Cone, RD et al., Recent Prog. Horm. Res., 51: 287-318 (1996)). [0006] MC1-R, known in the art as Melanocyte Stimulating Hormone Receptor (MSH-R), Melanotropic Receptor or Melanocortin-1 Receptor, is a 315 amino acid transmembrane protein belonging to the family of receptors coupled with the G. MC1-R protein. receptor for MSH and ACTH. The activity of MC1-R is mediated by G protein that activates adenyl cyclase. MC1-R receptors have been found in melanocytes and adrenocortical tissue as well as in many other tissues such as the adrenal gland.

Leukocytes, lung, lymph node, ovary, testes, pituitary, placenta, spleen and uterus. MC2-R, also referred to as the Adrenocorticotropic Hormone Receptor (ACTH-R), is a transmembrane protein of 297 amino acids found in melanocytes and adrenocortical tissue. MC2-R mediates the corticotropic effect of ACTH.

In humans, MC3-R is a 360 AA protein found in brain tissue; in mice and rats, MC3-R is a 323 AA protein. MC4-R is a transmembrane protein of 332 amino acids that is also expressed in the brain as well as in placental and intestinal tissues. MC5-R is a transmembrane protein of 325 amino acids, expressed in the adrenal glands, stomach, lungs and spleen, and at very low levels in the brain. MC5-R is also expressed in three layers of the adrenal cortex, mainly in aldosterone producing glomerular zone cells.

[0007] However, five known melanocortin receptors differ in function. For example, MC1-R is a G-protein coupled receptor that regulates pigmentation in response to α-MSH, a strong MC1-R agonist. Agonism at the MC1-R receptor causes melanocyte stimulation, which results in eumelanin production and increases the risk of skin cancer. Agonism against MC1-R may also have neurological effects. Stimulation of MC2-R activity may result in adrenal tissue cancer. Recent pharmacological studies have confirmed that central MC4-R receptors are the main mediators of anorexigenic and orexygenic activity attributed to melanocortin receptor agonists and antagonists, respectively. The effects of agonism on MC3-R and MC5-R are not yet known.

[0008] There is a great interest in melanocortin (MC-R) receptors as a goal to develop new therapeutic agents for treating weight disorders such as obesity and cachexia. Central, MC4-R receptors (Giraudo, SQ et al., Brain Res., 809: 302-306 (1998); Farooqi, IS et al., NE J Med., Are both genetic and pharmacological evidence. , 348: 1085-1095 (2003); MacNeil, DJ et al., Eu. Pharm., 44: 141-157 (2002); MacNeil, DJ et al., Eu. J. Pharm., 450: 93-109 (2002);

Kask, A. et al., NeuroReport, 10: 707-711 (1999)). Recent studies on receptor-selective agonists and antagonists confirm the therapeutic potential associated with melanocortin receptor activation, especially MC4-R.

[0009] Compounds that are agonists, antagonists or other ligands activating one or more melanocortin receptors will be useful for treating a wide variety of conditions in a patient in need thereof or at risk, including acute and chronic inflammatory diseases such as general inflammation (US Patent No. 6,613,874 ; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), inflammatory bowel disease (US Patent No. 6,713,487; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), encephalitis (Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), sepsis (US Patent No. 6,613,874; US Patent No. 6,713,487 ; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)) and septic shock (US Patent No. 6,613,874; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)); autoimmune diseases such as rheumatoid arthritis (US Patent No. 6,713,487; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), gouty arthritis (Catania, A. et al. , Pharm. Rev., 56: 1-29 (2004), Getting, SJ et al., Curr. Opin. Investig. Drugs, 2: 1064-1069 (2001)) and multiple sclerosis (US Patent No. 6,713,487); metabolic diseases and medical conditions associated with weight gain such as obesity (US Patent No. 6,613,874; US Patent No. 6,600,015; Fehm, HL et al., J. Clin. Endo. & Metab., 86: 1144-1148 (2001 ); Hansen, MJ et al., Brain Res., 1039: 137145 (2005); Ye, Z. et al., Peptides, 26: 2017-2025 (2005); Farooqi, IS et al., NE J Med., 348: 1085-1095

EP 2 236 151 B1 (2003); MacNeil, DJ et al., Eu. J. Pharm., 44: 141-157 (2002); MacNeil, DJ et al., Eu. J. Pharm., 450: 93-109 (2002); Kask, A. et al., NeuroReport, 10: 707-711 (1999); Schwartz, MW, J. Clin. Invest., 108: 963-964 (2001), Gura, T., Science, 287: 1738-1740 (2000), Raffin-Sanson, ML, Eu. J. Endo., 144: 207-208 (2001), Hamilton, BS et al., Obesity Res. 10: 182-187 (2002)), feeding disorders (US Patent No. 6,720,324; Fehm, HL et al., J. Clin. Endo. & Metab., 86: 1144-1148 (2001); Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15: 2541-2546 (2005)) and Prader-Willi syndrome (GE, Y. et al., Brain Research, 957: 42-45 (2002)); metabolic diseases and medical conditions associated with weight loss such as anorexia (US Patent No. 6,613,874; Wisse, BR et al., Endo., 142: 3292-3301 (2001)), bulimia (US Patent No. 6,720,324), cachexia associated with AIDS (Marsilje, TH et al., Bioorg. Med. Chem. Lett., 14: 3721-3725 (2004); Markison, S. et al., Endocrinology, 146: 2766-2773 (2005)), cachexia (US Patent No. 6,613,874; Lechan, RM et al., Endo., 142: 3288-3291 (2001); Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15: 2541-2546 (2005)), cancer-related cachexia (US Patent No. 6,639,123) and elderly cachexia (US Patent No. 6,639,123); c diabetes (US Patent No. 6,713,487) and conditions and complications associated with diabetes such as retinopathy (US Patent No. 6,525,019); tumor proliferation (US Patent No. 6,713,487) such as skin cancer (Sturm, RA, Melanoma Res., 12: 405-416 (2002); Bastiens, MT et al., Am. J. Hum. Genet., 68: 884 -894 (2001)) and prostate cancer (Luscombe, C. J. et al., British J. Cancer, 85: 1504-1509 (2001); medical conditions related to the reproductive or reproductive system such as endometriosis (US Patent No. 6,713,487) and uterine bleeding in women (US Patent No. 6,613,874), sexual dysfunction (US Patent No. 6,720,324; Van der Ploeg, LHT et al., PNAS, 99 : 11381-11386 (2002), Molinoff, PB et al., Ann.

NY Acad. Sci., 994: 96-102 (2003), Hopps, CV et al., BJU International, 92: 534-538 (2003)), erectile dysfunction (US Patent No. 6,613,874; Diamond, LE et al., Urology, 65 : 755-759 (2005), Wessells, H. et al., Int. J. Impotence Res., 12: S74-S79 (2000), Andersson, KE. Et al., Int. J. Impotence Res., 14 : S82-S92 (2002), Bertolini, A. et al., Sexual Behavior: Pharmacology and Biochemistry, Raven Press, NY, p. 247-257 (1975); Wessells, H. et al., Neuroscience, 118: 755 -762 (2003), Wessells, H. et al., Urology, 56: 641-646 (2000), Shadiack, AM et al., Society for Neuroscience Abstract, (2003); Wessells, H. et al., J. Urology, 160: 389-393 (1998), Rosen, RC et al., Int. J. Impotence Res., 16: 135-142 (2004), Wessells, H. and in., Peptydes, 26: 1972-1977 (2005)) and reduced sex drive in women (US Patent No. 6,713,487; Fourcroy, J. L., Drugs, 63: 1445-1457 (2003)); diseases or conditions caused by medical treatment or injury such as transplant rejection (US Patent No. 6,713,487; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), ischemia and reperfusion injury (Mioni, C . et al., Eu. J. Pharm., 477: 227-234 (2003); Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), treatment of spinal cord injury and acceleration wound healing (Sharma HS et al., Acta. Nerochir. Suppl., 86: 399-405 (2003); Sharma HS, Ann. NY Acad. Sci. 1053: 407-421 (2005); U.S. Patent No. 6,525,019), as well as weight loss caused by chemotherapy, radiation, periodic or prolonged immobilization (Harris, RB et al., Physiol. Behav., 73: 599-608 (2001)) or dialysis; cardiovascular diseases or conditions such as hemorrhagic shock (Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), cardiogenic shock (US Patent No. 6,613,874), hypovolemic shock (US Patent No. 6,613,874), cardiovascular disorders (US Patent No. 6,613,874) and cardiac cachexia (Markison, S. and et al., Endocrinology, 146: 2766-2773 (2005); lung diseases or conditions such as acute respiratory distress syndrome (US Patent No. 6,350,430; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), chronic obstructive pulmonary disease (US Patent No. 6,713,487), asthma (US Patent No. 6,713,487) and pulmonary fibrosis; to increase

EP 2 236 151 B1 of the immune system (Luger, TA et al., Pathobiology, 67: 318-321 (1999)) and to combat attacks on the immune system, such as attacks associated with certain allergies (US Patent No. 6,713,487) or with organ transplant rejection (US Patent No. 6,713,487; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)); for the treatment of dermatological diseases and conditions such as psoriasis (US Patent No. 6,713,487), loss of skin pigmentation (US Patent No. 6,713,487; Ye, Z. et al., Peptydes, 26: 2017-2025 (2005)), acne (Hatta, N. et al., J. Invest. Dermatol., 116: 564-570 (2001); Bohm, M. et al., J. Invest. Dermatol., 118: 533-539 (2002)), keloid formation (US Patent No. 6,525,019) and skin cancer (Sturm, RA, Melanoma Res., 12: 405-416 (2002); Bastiens, MT et al., Am. J. Hum. Genet., 68: 884-894 (2001)); behavioral and central nervous or neuronal disorders and disorders such as anxiety (US Patent No. 6,720,324; Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15: 2541-2546 (2005)), depression (Chaki, S. et al., Peptydes, 26: 1952-1964 (2005), Bednarek, MA et al., Expert Opinion Ther. Patents, 14: 327 -336 (2004); US Patent No. 6,720,324), memory impairment and impairment (US Patent No. 6,613,874; Voisey, J. et al., Curr. Drug Targets, 4: 586-597 (2003)), modulating pain perception (patent U.S. No. 6,613,874; Bertolini, A. et al., J. Endocrinol Invest., 4: 241-251 (1981); Vrinten, D. et al., J. Neuroscience, 20: 8131-8137 (2000)) and the treatment of neuropathic pain (Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15: 2541-2546 (2005)); conditions and diseases associated with alcohol consumption, alcohol abuse and / or alcoholism (WO 05/060985; Navarro, M. et al., Alcohol Clin. Exp. Res., 29: 949-957 (2005)); and renal disorders or diseases such as renal cachexia (Markison, S. et al., Endocrinology, 146: 2766-2773 (2005)) or natriuresis (US Patent No. 6,613,874).

[0010] Ligands activating one or more melanocorritin receptors will be useful for modulating many normalizing and homeostatic activities in a patient in need thereof, including thyroxine release (US Patent No. 6,613,874), aldosterone synthesis and release (US Patent No. 6,613,874), body temperature (US Patent No. 6,613,874), blood pressure (US Patent No. 6,613,874), heart rate (US Patent No. 6,613,874), vascular tone (US Patent No. 6,613,874), cerebral blood flow (US Patent No. 6,613,874), blood glucose levels (US Patent No. 6,613,874), bone metabolism, bone formation or development (Dumont, LM et al., Peptydes, 26: 1929-1935 (2005), ovarian weight (US Patent No. 6,613,874), placental development (US Patent No. 6,613,874), prolactin and FSH secretion (US Patent No. 6,613,874), intrauterine fetal development (US Patent No. 6,613,874), delivery (US Patent No. 6,613,874), spermatogenesis (US Patent No. 6,613,874), sebum and pheromone secretion (US Patent No. 6,613,874), neuroprotection (US Patent No. 6,639,123) and nerve growth (US Patent No. 6,613,874), as well as modulation of motivation (US Patent No. 6,613,874), learning (US Patent No. 6,613,874) and other behaviors (US Patent No. 6,613,874).

[0011] W02005 / 000339 A2 relates to MC4 receptor peptide agonists and their use for the treatment of disorders such as obesity, diabetes and sexual dysfunction in men and / or women.

[0012] Haskell-Luevano et al., J Med. Chem. 40: 1738-1748 (1997) describe the biological and conformational study of stereochemical modifications using the melanotropin peptide matrix, Ac-Nle-c [Asp-His-PheArg-Trp-Ala-Lys] -NH₂, on human melanocortin receptors.

[0013] Therefore, it is an object of the present invention to provide ligands for melanocortin receptors that exhibit greater stability and selectivity for melanocortin receptors than native melanocortin receptor ligands.

EP 2 236 151 B1

SUMMARY OF THE INVENTION [0014] In one aspect, the present invention relates to a melanocortin-4 receptor selective agonist compound having the formula:

Ac-Arg-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or diluent.

[0016] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for the treatment of acute or chronic inflammatory disease or condition selected from general inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock. In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating an autoimmune disease or condition, selected from rheumatoid arthritis, gouty arthritis and multiple sclerosis. In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a metabolic disease or condition accompanied by weight gain body selected from obesity, feeding disorders and Prader-Willi syndrome. In another aspect, the disease or condition being treated is obesity. In yet another aspect, the disease or condition being treated is a feeding disorder. In a further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for reducing food intake, for losing weight, or for obtaining a combination of these effects.

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a cancer disease or condition selected from cancer skin and cancer cachexia.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50, as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a condition associated with the reproductive system or sexual function selected from endometriosis, uterine bleeding, dysfunction of sexual function, erectile dysfunction and reduced sex drive in women.

[0019] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50, as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a disease or condition caused by treatment or injury of an organism, selected from organ transplant rejection, ischemia and reperfusion injury, spinal cord injury and injury, and weight loss caused by medical procedures selected from the group consisting of chemotherapy, radiotherapy, temporary or prolonged immobilization and dialysis.

[0020] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a cardiovascular disease or condition selected among hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.

[0021] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a lung disease or condition selected from acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.

[0022] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for increasing the tolerance of the immune system and for treating allergies .

[0023] In a further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a dermatological disease or condition selected from psoriasis , loss of skin pigmentation, acne and keloid formation.

[0024] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a behavioral disease, disease or condition central nervous system or neuronal disease selected from anxiety, depression, memory impairment and neuropathic pain.

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for treating a kidney disease or medical condition selected from renal cachexia and natriuresis.

[0026] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for the treatment of ovarian weight modulation, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, delivery, spermatogenesis, thyroxine release, aldosterone synthesis and release, temperature

Body fatigue, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth.

[0027] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for modulating bone metabolism, bone formation and bone development.

[0028] In a further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism or for treating alcohol addiction.

[0029] Also described herein is the use of a therapeutically effective amount of a melanocortin 4 selective agonist SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament useful for inhibiting alcohol consumption, for reducing alcohol consumption in a person in need thereof treating the patient.

[0030] Also described is a method of inducing agonist action at the melanocortin receptor in a patient in need thereof, which comprises administering to the patient an effective amount of a compound of SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt thereof.

[0031] In one aspect, the present invention provides a compound that is a selective melanocortin 4 receptor agonist, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of acute or chronic inflammatory disease or condition selected from general inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock.

[0032] In another aspect, the present invention provides a compound that is a selective melanocortin 4 receptor agonist, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of an autoimmune disease or condition, selected from rheumatoid arthritis, gouty arthritis and sclerosis sclerosis.

[0033] In another aspect, the present invention provides a compound that is a selective melanocortin 4 receptor agonist, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a metabolic disease or condition accompanied by a weight gain selected from obesity, feeding disorders and Prader-Willi syndrome. In a further aspect of the above use, the disease or condition is obesity. In yet another aspect of the above use, the disease or condition is a feeding disorder.

[0034] In another aspect, the present invention provides a compound that is a selective melanocortin 4 receptor agonist, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH2 (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use to reduce food intake, reduce weight or to obtain a combination of these effects.

In another aspect, the present invention provides a selective melanocortin 4 receptor agonist compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH2 (SEQ ID NO: ID: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a cancer disease or condition selected from skin cancer and cancer cachexia.

[0036] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH2 (SEQ ID NO: ID: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a condition associated with the reproductive system or sexual function selected from endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and reduced sex drive in women.

[0037] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a disease or condition caused by treatment or injury of an organism, selected from organ transplant rejection, ischemia and reperfusion injury, mutilation and injury spinal cord and weight loss caused by medical procedures selected from the group consisting of chemotherapy, radiation therapy, temporary or prolonged immobilization and dialysis.

[0038] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a cardiovascular disease or condition selected from hemorrhagic shock, cardiogenic shock, hypovolemic shock, disorders cardiovascular and cardiac cachexia.

[0039] In another aspect, the present invention provides a compound that is a selective melanocortin 4 receptor agonist, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a lung disease or condition selected from acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.

[0040] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such

An agonist or a salt thereof, as defined above, for use to increase the tolerance of the immune system or to treat allergies.

[0041] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof as defined above for use in the treatment of a dermatological disease or condition selected from psoriasis, loss of skin pigmentation, acne and keloid formation. [0042] In another aspect, the present invention provides a compound that is a selective melanocortin 4 receptor agonist, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a behavioral disease or disease of the central nervous or neuronal system or a condition selected from anxiety, depression, memory impairment and neuropathic pain.

In another aspect, the present invention provides a compound that is a selective melanocortin 4 receptor agonist, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in the treatment of a renal disease or disease state selected from renal cachexia and natriuresis.

[0044] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound, having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use for modulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, delivery, spermatogenesis, thyroxine release, synthesis and release of aldosterone, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth. [0045] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use in modulating bone metabolism, bone formation and bone development.

[0046] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such an agonist or a salt thereof, as defined above, for use for inhibiting alcohol consumption, reducing alcohol consumption, for treating alcoholism or alcohol dependence.

[0047] In another aspect, the present invention provides a melanocortin 4 receptor agonist selective compound having the formula: Ac - Arg - c (Cys - D - Ala - His - D - Phe - Arg - Trp - Cys) - NH₂ (SEQ ID NO: 50) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such

An agonist or a salt thereof, as defined above, for use in the treatment of diabetes mellitus and diabetes-related conditions or complications.

[0048] Also described herein is the use of a therapeutically effective amount of a melanocortin 4 selective agonist compound having the formula according to SEQ ID NO: 50 as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for treating a disease and / or condition selected from the group consisting of acute and chronic inflammatory diseases such as general inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock; autoimmune diseases such as rheumatoid arthritis, gouty arthritis and multiple sclerosis; metabolic diseases and disease disorders accompanied by weight gain such as obesity, feeding disorders and Prader-Willi syndrome; cancer cachexia; diabetes, conditions and complications associated with diabetes such as retinopathy; tumor proliferation such as skin cancer and prostate cancer; conditions related to the reproductive system and sexual function, such as endometriosis and uterine bleeding in women, sexual dysfunction, erectile dysfunction and reduced sex drive in women; diseases and conditions caused by treatment or damage to the body, such as organ transplant rejection, ischemia and reperfusion injury, spinal cord injury and mutilation, as well as weight loss due to chemotherapy, radiotherapy, temporary or prolonged immobilization and dialysis; cardiovascular diseases or conditions such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia; lung diseases or conditions such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, asthma and pulmonary fibrosis; to increase the tolerance of the immune system and to combat attacks on the immune system, such as those associated with certain allergies or organ transplant rejection; for the treatment of dermatological diseases and conditions such as psoriasis, loss of skin pigmentation, acne, keloid formation and skin cancer; for the treatment of behavioral disorders and central nervous and neuronal disorders such as anxiety, depression, memory impairment and neuropathic pain; for the treatment of kidney diseases and conditions such as renal cachexia and natriuresis.

[0049] Also described herein is the use of a therapeutically effective amount of a melanocortin 4 selective agonist compound having the formula according to SEQ ID NO: 50, as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for modulating normalizing or homeostatic activities such as ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, delivery, spermatogenesis, thyroxine release, synthesis and aldosterone release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection, nerve growth, bone metabolism, bone formation and bone development.

[0050] It should be emphasized that therapeutic interventions undertaken in both normal physiological and pathophysiological processes involving melanocortin receptors are also considered.

[0051] Other objects, advantages and features of the present invention will become apparent from the following description and the appended claims in combination with the accompanying drawings.

[0052] Described here:

EP 2 236 151 B1

- compounds of formula (I):

(R²R³)-AND¹-C (A²-AND³-AND⁴-AND⁵-AND⁶-AND⁷-AND⁸-AND⁹)-AND¹⁰-R¹ wherein:

₁

A is Acc, HN- (CH₂)_m-C (O), L- or D-amino acid, or is absent;

AND² is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;

₃

A is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or is absent;

AND⁴ means His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X¹X²X³X⁴X⁵) Phe;

AND⁵ means D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D- (X¹X²X³X⁴X⁵) Phe, L-Phe or D- (Et) Tyr;

AND⁶ means Arg, hArg, Dab, Dap, Lys, Om or HN-CH ((CH2) nN (R⁴R⁵))-WHAT);

AND⁷ is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal or D-Bip;

AND⁸ means Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN- (CH₂)_s-C (O), or is absent;

AND⁹ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Om or Lys;

A is Acc, HN- (CH₂)_t-C (O), L- or D-amino acid, or is absent;

R¹ is -OH or -NH₂;

each R and R in each case is independently selected from the group consisting of H, (C₁-C₃₀) alkyl, (C1-C₃o) heteroalkyl, (C₁-C₃₀) acyl, (C₂-C₃₀) alkenyl, (C₂-C₃₀) alkynyl, aryl (C₁-C₃₀) alkyl, aryl (C₁-C₃₀) acyl, substituted (C₁-C₃₀) alkyl, substituted (C₁-C₃₀) heteroalkyl, substituted (C₁-C₃₀) acyl, substituted (C₂-C₃₀) alkenyl, substituted (C₂-C₃₀) alkynyl, substituted aryl (C₁-C₃₀) alkyl and substituted aryl (C₁-C₃₀) Acyl;

each R and R in each case is independently H, (C₁-C₄₀) alkyl, (C₁-C₄₀) heteroalkyl, (C₁-C₄₀) acyl, (C₂-C₄₀) alkenyl, (C₂-C₄₀) alkynyl, aryl (C₁-C₄₀) alkyl, aryl (C₁-C₄₀) acyl, substituted (C₁-C₄₀) alkyl, substituted (C₁-C₄₀) heteroalkyl, substituted (C₁-C₄₀) acyl, substituted (C₂-C₄₀) alkenyl, substituted (C₂-C₄₀) alkynyl, substituted aryl (C₁-C₄₀) alkyl, substituted aryl (C₁-C₄₀) acyl, (C₁-C₄₀) alkylsulfonyl or -C (NH) -NH₂; m independently in each case means 1,2, 3, 4, 5, 6 or 7;

n is independently in each case 1,2, 3, 4 or 5;

s independently in each case means 1,2, 3, 4, 5, 6 or 7;

t is in each case 1,2, 3, 4, 5, 6 or 7;

every X¹, X², X³, X⁴ and X⁵ independently in each case means H, F, Cl, Br, I, (C₁-₁₀) alkyl, substituted (C_1-10) alkyl, (C_2-10) alkenyl, substituted (C_2-10) alkenyl, (C_2-10) alkynyl, substituted (C_2-10) alkynyl, aryl, substituted aryl, OH, NH₂, NO₂ or CN; provided that (I) when R⁴ means (C₁-C₄₀) acyl, aryl (C.₁-C₄₀) acyl, substituted (C₁-C₄₀) acyl, substituted aryls₅ lo (C₁-C₄₀) acyl, (C₁-C₄₀) alkylsulfonyl, or -C (NH) -NH₂, then R is H or (C₁-C₄₀) alkyl, (C₁-C₄₀) heteroalkyl, (C₂-C₄₀) alkenyl, (C₂-C₄₀) alkynyl, aryl (C₁- C.₄₀) alkyl, substituted (C₁-C₄₀) alkyl, substituted (C₁-C₄₀) heteroalkyl, substituted (C₂-C₄₀) alkenyl, substituted (C₂-C₄₀) alkynyl or substituted aryl (C1-C40) alkyl;

₂ (II) when R is (C₁-C₃₀) acyl, aryl (C.₁-C₃₀) acyl, substituted (C₁-C₃₀) acyl or substituted ₃ aryl (C₁-C₃₀) acyl, then R is H, (C₁-C₃₀) alkyl, (C₁-C₃₀) heteroalkyl, (C₂-C₃₀) alkenyl, (C₂-C₃₀) alkynyl, aryl (C₁-C₃₀) alkyl, substituted (C₁-C₃₀) alkyl, substituted (C₁-C₃₀) heteroalkyl, substituted (C₂-C₃₀) alkenyl, substituted (C₂-C₃₀) alkynyl or substituted aryl (C₁-C₃₀) Alkyl;

(III) A.³ or A⁸ or both of them must be present in the relationship;

(IV) when A² means Cys, D-Cys, hCys, D-hCys, Pen or D-Pen, then A⁹ is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen;

(V) when A² is Asp or Glu, then A⁹ is Dab, Dap, Om or Lys;

(VI) when A⁸ means Ala or Gly, then A¹ does not mean Nle; and (VII) when A is absent, R and R cannot be H at the same time; or a pharmaceutically acceptable salt thereof;

and

- compounds of formula (II):

(R²R³)-AND¹-C (A²-AND³-AND⁴-AND⁵-AND ⁶-AND⁷-AND⁸-AND⁹) -NH in which:

₁

AND¹ is Nle or is absent;

₂

AND² is Cys or Asp;

AND³ is Glu or D-Ala;

AND⁴ is His;

AND⁵ is D-Phe;

AND⁶ is Arg;

AND⁷ is Trp, 2-Nal or Bal;

AND⁸ is Gly, Ala, D-Ala, β-Ala, Gaba or Apn;

AND⁹ is Cys or Lys;

each R and R is independently selected from the group consisting of H or (C₁-C₆) Acyl;

provided that (I) when R is (C₁-C₆) acyl, then R is H; and (II) when A is Cys, then A is Cys, or a pharmaceutically acceptable salt thereof.

[0053] The compounds of formula (I) or (II) are ligands of at least one of the melanocortin receptors (MC1-R, MC2-R, MC3-R, MC4-R and MC5-R) and selection of these compounds, including an agonist according to the invention, the tests for the ability to act as a ligand in vitro described below were carried out.

BRIEF DESCRIPTION OF THE DRAWINGS:

[0054]

Figure 1A: Mean difference in food consumed in fasting rats after 6 hours after administration of 100 nmol / kg selected compounds compared to vehicle.

Figure 1B. Mean difference in food consumed in fasting rats after 6 hours after administration of 500 nmol / kg selected compounds compared to vehicle.

Figure 2A. Cumulative difference in mean food intake in rats after administration of different concentrations of Compound A compared to vehicle.

EP 2 236 151 B1

Figure 2B. The cumulative difference in mean body weight in rats after administration of different concentrations of Compound A compared to vehicle.

Figure 3A. Cumulative difference in mean food intake in rats after administration of selected compounds compared to vehicle.

Figure 3B. The cumulative difference in mean body weight in rats after administration of selected compounds compared to vehicle.

Figure 4A. Cumulative difference in mean food intake in rats after administration of selected compounds compared to vehicle.

Figure 4B. The cumulative difference in mean body weight in rats after administration of selected compounds compared to vehicle.

DETAILED DESCRIPTION OF THE INVENTION [0055] Here, the typical nomenclature used in the technique was used to determine the peptides, according to which the amino group at the N-terminal is present on the left and the carboxyl group on the C-terminal is on the right. Unless specifically indicated otherwise, when the amino acid has isomeric forms, it means the L form of the amino acid. Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly accepted by one of ordinary skill in the art to which the invention belongs. Also all publications, patent applications, patents and other references cited are incorporated herein by reference.

Nomenclature and abbreviations [0056]

<td>Symbol</td><td>Importance</td>

<td>abu</td><td>α-aminobutyric acid</td>

<td>ac</td><td>acyl group</td>

<td>Acc</td><td>1-amino-1-cycloic acid (C.₃-C₉) the alkyl</td>

<td>A3c</td><td>1-amino-1-cyclopropane carboxylic acid</td>

<td>A4C</td><td>1-amino-1-cyclobutanecarboxylic acid</td>

<td>A5c</td><td>1-amino-1-cyclopentanecarboxylic acid</td>

<td>A6c</td><td>1-amino-1-cyclohexane carboxylic acid</td>

<td>yep</td><td>7-aminoheptanoic acid</td>

<td>Ahx</td><td>6-aminohexanoic acid</td>

<td>b</td><td>α-aminoisobutyric acid</td>

<td>Ala or A.</td><td>alanine</td>

EP 2 236 151 B1

Importance

The β-Ala symbol

apn

Arg or R hArg

Asn or N

Asp or D

Ball

bip

Bishop

4-Br-Phe

Cha hCha

Chg

Cys or C hCys

Oak

dap

Dip

Doc β-alanine 5-aminopentanoic acid (HN- (CH2)₄-C (O) arginine homoarginine asparagine aspartic acid

3-benzotienyloalanina

4,4'-biphenylalanine, represented by the formula

<img file="PL2236151T3_D0001.tif" />

4-bromo-phenylalanine

8-cyclohexylalanine homo-cyclohexylalanine cyclohexylglycine cysteine ​​homocysteine ​​2,4-diaminobutyric acid 2,3-diaminopropionic acid β, β-diphenylalanine 8-amino-3,6-dioxaacetic acid with the formula:

<img file="PL2236151T3_D0002.tif" />

EP 2 236 151 B1

Symbol Meaning

<td>2-Fua</td><td>β- (2-furyl) -alanine,</td>

<td>Gaba</td><td>4-aminobutyric acid</td>

<td>Gln or Q</td><td>glutamine</td>

<td>Glu or E</td><td>glutamic acid</td>

<td>Gly or G</td><td>glycine</td>

<td>His or H</td><td>histidine</td>

<td>3-Hyp</td><td>trans-3-hydroxy-L-proline, i.e., (2S, 3S) -3-hydroxypyrrolidine-2-carboxylic acid</td>

<td>4-Hyp</td><td>4-hydroxyproline, i.e., (2S, 4R) -4-hydroxypyrrolidine-2-carboxylic acid</td>

<td>How much or</td><td>isoleucine</td>

<td>Leu or L</td><td>leucine</td>

<td>hLeu</td><td>homoleucyna</td>

<td>Lys or K</td><td>lysine</td>

<td>Met or M.</td><td>methionine</td>

<td>β-hMet</td><td>β-homometionina</td>

<td>1-Nal</td><td>β- (1-naphthyl) alanine:</td>

<td>2-Nal</td><td>β- (2-naphthyl) alanine</td>

<td>nip</td><td>nipecotinic acid</td>

<td>Nle</td><td>norleucine</td>

<td>oic</td><td>octahydroindole-2-carboxylic acid</td>

<td>Ohm</td><td>ornithine</td>

<td>2-Pal</td><td>β- (2-pyridyl) alanine</td>

<td>3-Pal</td><td>β- (3-pyridyl) alanine</td>

<td>4-Pal</td><td>β- (4-pyridyl) alanine</td>

<td>Pen</td><td>penicillamine</td>

<td>Phe or F</td><td>phenylalanine</td>

<td>HPhe</td><td>homophenylalanine</td>

<td>Pro or P</td><td>proline</td>

<td>hPro</td><td>homoproline</td>

<td>Cheese or S</td><td>serine</td>

EP 2 236 151 B1

Symbol Meaning

<td>background</td><td>tert-Leucine</td>

<td>Taz</td><td>p- (4-thiazolyl) alanine</td>

<td>2-Thi</td><td>p- (2-thienyl) alanine</td>

<td>3-Thi</td><td>p- (3-thienyl) alanine</td>

<td>Thr or T.</td><td>threonine</td>

<td>Trp or W</td><td>tryptophan</td>

<td>Tyr or Y</td><td>tyrosine</td>

<td>D- (Et) Tyr</td><td>has a pattern</td>

<img file="PL2236151T3_D0003.tif" />

Val or V valine [0057]

Boc:

Bzl:

DCM:

DIC:

DIEA:

Dmab:

DMAP:

DMF:

DNP:

fm:

Fmoc:

for:

HBTU:

cHex:

HOAT:

HOBt:

MBHA

mmt:

Some of the other abbreviations used herein have the following meanings: tert-butyloxycarbonyl benzyl dichloromethane

N, N-diisopropylcarbodiimide, diisopropylethylamine

4- {N- (1- (4,4-dimethyl-2,6-dioksocykloheksylideno) -3-methylbutyl) -amino} benzyl

4- (dimethylamino) pyridine dimethylformamide

2,4-dinitrophenyl fluorenylmethyl fluorenylmethyloxycarbonyl formyl hexafluorophosphate 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium cyclohexyl hexafluorophosphate O- (7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium

hydroxy-benzotriazole

4-methylbenzhydrylamine

4-methoxytrityl

EP 2 236 151 B1

NMP: N-methylpyrrolidone

O-tBu: oxy-tert-butyl

Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

PyBroP: bromo-tris-pyrrolidine-phosphonium hexafluorophosphate tBu: tert-butyl

TIS: triisopropylsilane

TOS: tosyl

Trt: trityl

TFA: trifluoroacetic acid

TFFH: tetramethylfluoroforamidinium hexafluorophosphate

Z: benzyloxycarbonyl [0058] Unless otherwise indicated, except for the N-terminal amino acid, in this disclosure all abbreviations (e.g., Ala) of the amino acids are -NH-C (R) (R ') - CO-, wherein each R and R 'is independently hydrogen or an amino acid side chain (e.g., R = CH₃, R '= H for Ala), or R and R' can be joined and can form a ring system.

[0059] For the N-terminal amino acid, the abbreviation means the following structure:

<img file="PL2236151T3_D0004.tif" />

[0060] The designation "NH₂". e.g. in Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂, indicates that the C-terminus of the peptide is amidated. Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) or alternatively Ac-Nle-c (Cys-D-AlaHis-D-Phe-Arg-Trp-Cys) -OH , indicates that the C-terminus is a free amino acid.

[0061] "-c (Cys-Cys) -" or "-cyclo (Cys-Cys) -" means the structure:

<img file="PL2236151T3_D0005.tif" />

"-c (Cys-Pen) -" or "-cyclo (Cys-Pen) -" means structure:

<img file="PL2236151T3_D0006.tif" />

"-c (Asp-Lys) -" or "-cyclo (Asp-Lys) -" means the structure:

<img file="PL2236151T3_D0007.tif" />

[0062] "Acyl" refers to R "-C (O) -, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl , and in the general formula in a particular embodiment is indicated as "Ac".

[0063] "Alkyl" refers to a hydrocarbon group containing one or more carbon atoms in which, when multiple carbon atoms are present, they are connected by single bonds. The alkyl hydrocarbon group may be straight chain or may contain one or more branching or cyclic groups.

[0064] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms of the hydrocarbon group has been replaced by one or more hydroxyl radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc.

[0065] "Substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms of the hydrocarbon group has been replaced by one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine and iodine), -OH, CN, -SH, -NH2, -NHCH3, -NO2 and -C1-20 alkyl, wherein -C1-20 alkyl may be optionally substituted with one or more substituents independently and in each case selected from the group consisting of halogens, -CF3, -OCH3 , -OCF3 and - (CH2) 0-20-COOH. In various embodiments 1, 2, 3 or 4 substituents are present. The presence of - (CH2) 0-20-COOH leads to the formation of an alkyl acid. Non-limiting examples of alkyl acids containing, or consisting of - (CH2) 0-20-COOH, include 2-norbornanoacetic acid, tert-butyric acid, 3-cyclopentylpropionic acid, etc.

[0066] The term "halogen" includes fluorine, chlorine, bromine and iodine.

[0067] "Heteroalkyl" refers to an alkyl in which one or more carbon atoms in the hydrocarbon group has been replaced by one or more of the following groups: amino, amide,

-O-, -S- or carbonyl. 1 or 2 heteroatoms are present in various embodiments.

[0068] "Substituted heteroalkyl" refers to a heteroalkyl in which one or more hydrogen atoms of the hydrocarbon group is replaced by one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN , -SH, -NH₂, -NHCH₃, -NO₂ and -C_1-20 alkyl, with -C_1-20 alkyl may optionally be substituted with one or more substituents independently selected in each case from the group consisting of halogens, -CF₃, -OCH₃, -OCF₃ their₂)_0-20COOH. In various embodiments 1, 2, 3 or 4 substituents are present.

[0069] "Alkenyl" refers to a hydrocarbon group consisting of two or more carbon atoms in which one or more carbon-carbon double bonds are present. The alkenyl hydrocarbon group may be straight chain or may contain one or more branches or cyclic groups.

[0070] "Substituted alkenyl" refers to alkenyl in which one or more hydrogen atoms are replaced by one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH , -NH₂, -NHCH₃, -NO₂ and -C_1-20 alkyl, with -C_1-20 alkyl may optionally be substituted with one or more substituents independently selected in each case from the group consisting of halogens, -CF₃, -OCH₃, -OCF₃ their₂)_0-20COOH. In various embodiments 1,2, 3 or 4 substituents are present.

[0071] "Aryl" refers to an optionally substituted aromatic group with at least one ring containing a conjugated pi electron system, containing up to three conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5- or 6-membered ring. Preferred at hetero 18 in heterocyclic aryl

Mum are one or more sulfur, oxygen and / or nitrogen atoms. Non-limiting examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, etc. The aryl substituents are selected from the group consisting of -C_1-20 alkyl, -C_1-20 alkoxy, halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH₂, -NO₂, -C_1-20 halogen substituted alkyl, -CF₃, -OCF₃ their₂)_0-20COOH. In various embodiments, aryl has 0, 1, 2, 3 or 4 substituents.

[0072] "Alkylaryl" refers to "alkyl" attached to "aryl".

[0073] The term "residue (C₁-C₁₂hydrocarbyl "includes alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl it is the residue C₂-C₁₂.

[0074] The term "normalizing" functions or activities as used herein refers to those functions that are considered to be associated with the proper functioning or homeostasis of the body. Such functions include, but are not limited to, activities and functions that condition body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose levels, etc.

[0075] According to current use, compounds that are considered "selective" for a given melanocortin receptor are compounds with functional activity characterized by an EC value₅₀which is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 17 times, at least about 90 times, at least about 200 times, at least about 3000 times or at least about 10,000 times or even above, selectivity for a given melanocortin receptor compared to any other melanocortin receptor. For example, the selective melanocortin 4 receptor agonist exhibits functional activity characterized by an EC value₅₀according to which the compound is at least about 15 times more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor. Also, for example, the selective melanocortin 4 receptor agonist according to the invention has activity functional characterized by EC value₅₀according to which it is at least 17 times more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

Synthesis [0076] The peptides described herein can be prepared by a standard solid phase peptide synthesis method, See, e.g., Stewart, JM, et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984). In the above generic formula, the R and R substituents can be attached to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, e.g. (C₁-C₃₀) alkyl, can be attached using reductive alkylation. Hydroxyalkyl groups, e.g., (C₁-C₃₀) hydroxyalkyl, can also be attached using reductive alkylation, the hydroxyl group being protected ₁ t-butyl ester. Acyl groups, e.g., COE, can be attached by coupling of a free acid, e.g.,₁

E COOH, with the free amine of the N-terminal amino acid by mixing for one hour all of the resin with 3 molar equivalents of free acid and diisopropylcarbodiimide in methylene chloride. If the free acid contains a free hydroxyl group, e.g. p-hydroxyphenylpropionic acid, then the coupling should be carried out using an additional 3 molar HOBt equivalents.

[0077] When R is -NH₂, peptide synthesis begins with an Fmoc-amino acid that conjugates with ₁ Rinka MBHA amide resin. When R is -OH, peptide synthesis begins with a Fmocamino acid that couples with Wang resin.

[0078] In the synthesis of a peptide of the invention containing A6c and / or Aib, the coupling time for these residues I for the residue immediately after them is 2 hours.

[0079] The following examples describe synthetic methods for producing the peptide described herein that are well known to those skilled in the art. Other methods are also known to those skilled in the art. The examples are provided for the purpose of illustration only and in no way limit the scope of the present invention.

EXAMPLES

Example 1: Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH, SEQ ID NO: 1. [0080] The title peptide was synthesized using the Advanced ChemTech model 396 multiple peptide synthesizer (Louisville, KY 40228) peptide synthesizer, using a fluorenylmethyloxycarbonyl (Fmoc) group. Rink's amide resin, 4-methylbenzylhydrylamine (MBHA), (Novabiochem, San Diego, CA) was used with a substitution of 0.58 mmol / g. As Fmoc-amino acids (Novabiochem, CA and ChemImpex®, IL) Fmoc-Nle-OH, Fmoc-Cys (Trt) -OH, Fmoc-D-Ala-OH, Fmoc-His (Trt) -OH, Fmoc-D were used -PheOH, Fmoc-Arg (Pbf) -OH and Fmoc-Trp (Boc) -OH. The synthesis was carried out on a 0.035 mmol scale. The Fmoc groups were removed by treatment for 30 minutes with a 25% solution of piperidine in ^ - dimethylformamide (DMF). At each coupling step, Fmoc-amino acid (10 equivalents, 0.35 mmol), N, N-diisopropylcarbodiimide (DIC) (10 equivalents, 0.35 mmol) and 1-hydroxy-benzotriazole (HOBt) (10 equivalents, 0.35 mmol) ) was used in DMF (1.4 ml). After washing with DMF, double coupling was carried out using Fmoc-amino acid (10 equivalents, 0.35 mmol), 2- (1-Hbenzotriazol-1-yl) -1,1,2,3-tetramethyluronium hexafluorophosphate (HBTU) (8 equivalents, 0.28 mmol), HOBT (10 equivalents, 0.35 mmol) and diisopropylethylamine (DIEA) (20 equivalents, 0.7 mmol) in DMF (1.26 mL). The ACT 396 multiple peptide synthesizer peptide synthesizer was programmed to run the following reaction cycle: (1) washing with DMF, (2) removing the Fmoc protecting group using a 25% solution of piperidine in DMF for 30 minutes, (3) washing with DMF, (4) coupling with Fmoc-amino acid in the presence of DIC and HOBT for 1 hour, (5) washing with DMF, (6) double coupling with the same Fmoc-amino acid from step 4 in the presence of HBTU, HOBt and DIEA for 1 hour.

Coupling on the resin was carried out sequentially according to the title peptide sequence. After assembling the peptide chain, the last Fmoc protective group was removed and the resin was completely washed using DMF and dichloromethane (DCM).

[0081] To cleave the title peptide, the resin was treated with a solution (1.5 ml) of TFA, H for 2 hours at room temperature₂O and triisopropylsilane (TIS) (v / v / v: 90 / 6.2 / 3.8).

The resin was filtered off and the filtrate was poured into 30 ml of ether. The precipitate was collected by centrifugation. The resulting crude product was dissolved in water (about 7 mL) and the pH of the aqueous solution was adjusted to about 7.5 by the addition of 2N NH₄HCO₃. The solution was exposed to air for 72 hours at a temperature of 20

EP 2 236 151 B1. The resulting crude product was purified by reverse phase preparative HPLC on a column (4 x 43 cm) C₁₈ DYNAMAX-100® A⁰ (Varian®, Walnut Creek, CA). The column was eluted for about 1 hour using a linear gradient of 85% A: 15% B to 30% A: 70% B, where A is a 0.1% solution of TFA in water, B is a 0.1% solution of TFA in acetonitrile. Fractions were tested by analytical HPLC and fractions containing the pure product were collected and lyophilized to dryness to give 10.3 mg (27% yield) of a white solid. The purity was tested by HPLC and found to be around 88%. According to electrospray mass spectrometry (ESI-MS), the molecular weight is 1073.6 (and is consistent with the calculated molecular weight of 1074.3).

Example 2: Ac-Cha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂ SEQ. [0082] The title peptide was synthesized using the Applied Biosystems peptide synthesizer (Foster City, CA) model 430A peptide synthesizer, which was modified to accelerate solid phase peptide synthesis using the Boc group. See, Schnolzer, et al., Int. J. Peptide Protein Res., 40: 180 (1992). The resin used was 4-methylbenzhydrylamine (MBHA) (Peninsula, Belmont, CA) with a substitution of 0.91 mmol / g. As Boc-amino acids (Novabiochem®, San Diego, CA and Chem-Impex®, Wood Dale, IL) were used: Boc-Cha-OH, Boc-Asp (OFm) -OH, Boc-His (DNP) -OH, Boc -D-Phe-OH, Boc-Arg (Tos) -OH, BocTrp (For) -OH, Boc-Gaba-OH and Boc-Lys (Fmoc) -OH. The synthesis was carried out on a 0.20 mmol scale. Boc groups were removed by treatment 2 times for 1 minute with 100% TFA. Boc-amino acids (2.5 mmol) were preactivated using HBTU (2.0 mmol) and DIEA (1.0 ml) in 4 ml DMF and coupled without prior neutralization of the peptide-resin TFA salt. Coupling times were 5 minutes.

[0083] At the end of the assembly of Boc-Asp (OFm) -His (DNP) -D-Phe-Arg (Tos) -Trp (For) -Gaba-Lys (Fmoc) -MBHA, the peptide-resin was transferred to the reaction vessel on a shaker . The resin was treated twice with 25% piperidine in DMF for 15 minutes per session, washed with DMF and shaken with bromo-tris-pyrrolidine-phosphonium hexafluorophosphate (PyBrOP) (6 equivalents, 0.3 mmol), DIEA (1 mL) and 4- (dimethylamino) pyridine (DMAP) (24 mg) in DMF (2 ml) for 12 hours. After washing with DMF, the resin was treated with 100% TFA solution twice each time for 2 minutes; washed with DMF and DCM and then dried under reduced pressure. A quarter of the peptide-resin (0.05 mmol) was used for the next coupling step with Boc-Cha-OH (10 equivalents, 0.5 mmol) in the presence of HBTU (9 equivalents, 0.45 mmol) and DIEA (0.25 ml) ) in DMF for 10 minutes. After deprotection using 100% TFA in two sessions, each lasting about 2 minutes, the peptide-resin was washed with DMF. The final blocking step was carried out by shaking the resin for 1 hour with acetic anhydride (40 equivalents, 2.0 mmol) and DIEA (20 equivalents, 1.0 mmol) in DMF. After washing with DMF to remove the DNP group in the histidine side chain, the resin was treated twice with a solution of 20% mercaptoethanol / 10% DIEA in DMF, each treatment lasting about 30 minutes. The formyl group on the tryptophan side chain was removed by shaking twice 30 minutes with a solution of 15% ethanolamine / 15% water / 70% DMF. The peptide resin was washed with DMF and DCM and dried under reduced pressure. Final cleavage was carried out by mixing the peptide-resin in 10 ml HF containing 1 ml anisole and dithiothreitol (30 mg) at 0 ° C for 75 minutes. HF was removed under a flow of nitrogen. The residue was washed with ether (6 x 10 mL) and extracted with 4N HOAc (6 x 10 mL).

[0084] The peptide mixture in the aqueous extract was purified by reverse phase preparative high performance liquid chromatography (HPLC) on a VYDAC® C column₁₈ (Nest Group®, Southborough, MA). The column was eluted with a linear gradient (10% to 50% solution B over 40 minutes) at a flow rate of 10 ml / minute (Solution A = water containing 0.1% TFA; Solution B = acetonitrile containing 0.1% TFA). Fractions were collected and tested by analytical HPLC. Fractions containing pure product were combined and lyophilized to dryness. 5.1 mg of a white solid were obtained. The yield was 8.9%. According to HPLC analysis, the purity was 94.5%. According to the electrospray mass spectrometry (MS (ES)) analysis, the molecular weight was 1148.5 (compliance with the calculated molecular weight of 1148.3).

[0085] Using synthetic methods analogous to those generally disclosed above and / or specifically disclosed in the examples, one skilled in the art can produce other peptides as described herein, such as the compounds shown in Tables 1A and 1B.

[0086] One skilled in the art can make other peptides using synthetic methods analogous to those disclosed generally above and / or specifically disclosed in the examples by which the compounds shown in Tables 1A and 1B were prepared.

[0087] The following compounds can be prepared according to the appropriate procedures described above: Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-e-Ala-Lys) -NH2; SEQ. ID NO: 1 Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-A6c-Lys) -NH2; SEQ. ID NO: 1 Ac-Nle-c (Cys-His-D-Phe-Arg-Trp-Ahx-Cys) -NH2; SEQ. ID NO: 2 D-Phe-c (Cys-His-D-Phe-Arg-Trp-Ata-D-Cys) -Thr-NH2; SEQ. ID NO: 3 D-Phe-c (Cys-His-D-Phe-Arg-Trp-e-Ala-D-Cys) -Thr-NH₂; SEQ. ID NO: 3 D-Phe-c (Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys) -Thr-NH2; SEQ. ID NO: 3 Ac-Nle-c (Cys-His-D-Phe-Arg-Trp-Apn-Cys) -NH2; SEQ. ID NO: 2 Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-Apn-Lys) -NH2; SEQ. ID NO: 4 Ac-A6c-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH2; SEQ. ID NO: 5 Ac-D-2-Nal-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH2; SEQ. ID NO: 6 Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH2; SEQ. ID NO: 6 Ac-Nle-c (Cys-p-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 7 Ac-Nle-c (Cys-Gaba-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 7 Ac-Nle-c (Cys-Aib-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 7 Ac-Nle-c (Cys-Gly-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 7 Ac-Nle-c (D-Cys-Ala-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 8 Ac-Nle-c (D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 8 Ac-Nle-c (D-Cys-p-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 8 Ac-Nle-c (D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 8 Ac-Nle-c (D-Cys-Aib-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ ID NO. ID NO: 8 Ac-Nle-c (D-Cys-Gly-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ ID NO. ID NO: 8 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys) -NH2; SEQ. ID NO: 9 Ac-Nle-c (Cys-p-Ala-His-D-Phe-Arg-Trp-D-Cys) -NH2; SEQ. ID NO: 9 Ac-Nle-c (Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys) -NH2; SEQ. ID NO: 9

EP 2 236 151 B1

Ac-Nle-c (Cys-Aib-His-D-Phe-Arg-Trp-D-Cys) -NH2; SEQ ID NO. ID NO: 9 Ac-Nle-c (Cys-Gly-His-D-Phe-Arg-Trp-D-Cys) -NH2; SEQ ID NO: 9 ID NO: 9 Ac-Nle-c (D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys) -NH₂; SEQ. ID NO: 10 Ac-Nle-c (D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys) -NH₂; SEQ. ID NO: 10 Ac-Nle-c (D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys) -NH₂; SEQ. ID NO: 10 Ac-Nle-c (D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys) -NH₂; SEQ. ID NO: 10 Ac-Nle-c (D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys) -NH₂; SEQ. ID NO: 10 Ac-Oic-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-Chg-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ ID NO. ID NO: 11 Ac-hCha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-D-Cha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-Nip-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. NR ID: 11 Ac-hPro-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-hLeu-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-hCha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-Phe-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-D-Phe-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-D-Chg-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 n-butanoyl-Cha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 12 Ac-hPhe-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-β-hMet-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-Gaba-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 11 Ac-Cha-c (Asp-His-D-Phe-Arg-D-Trp-Ala-Lys) -NH₂; SEQ. ID NO: 13 Ac-hCha-c (Asp-His-D-Phe-Arg-D-Trp-Ala-Lys) -NH₂; SEQ. ID NO: 13 Ac-Leu-c (Asp-His-D-Phe-Arg-D-Trp-Ala-Lys) -NH₂; SEQ. ID NO: 13 Ac-hLeu-c (Asp-His-D-Phe-Arg-D-Trp-Ala-Lys) -NH₂; SEQ. ID NO: 13 Ac-Phe-c (Asp-His-D-Phe-Arg-D-Trp-Ala-Lys) -NH₂; SEQ. ID NO: 13 Ac-Nle-c (Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys) -NH₂; SEQ. ID NO: 14 Ac-Nle-c (Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys) -NH₂; SEQ. ID NO: 14 Ac-Nle-c (Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 14 Ac-Nle-c (Asp-His-D-Phe-Arg-D-Trp-Aha-Lys) -NH₂; SEQ. NR ID: 14 ​​Ac-Nle-c (Asp-His-D-Phe-Arg-D-Trp-Apn-Lys) -NH₂; SEQ. ID NO: 14 Ac-Nle-c (Cys-Nis-D-Phe-Arg-D-Trp-Apn-Cys) -NH₂; SEQ. ID NO: 15 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys) -NH₂; SEQ. ID NO: 15 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys) -NH₂; SEQ. ID NO: 15 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys) -NH₂; SEQ. ID NO: 15 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys) -NH₂; SEQ. ID NO: 15 Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 16 Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys) -NH₂; SEQ. ID NO: 16 Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys) -NH₂; SEQ. ID NO: 16

EP 2 236 151 B1 n-butanoyl-Nle-c (Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys) -NH₂ SEQ. ID NO: 17 n-butanoyl-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 17 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys) -NH₂; SEQ. ID NO: 18 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys) -NH₂; SEQ. ID NO: 18 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Bal-Cys) -NH₂; SEQ. ID NO: 18 Ac-Nle-c (Cys-D-Glu-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 61 Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-D-Ala-Lys) -NH₂; SEQ ID NO. ID NO: 19 Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys) -NH2; SEQ. ID NO: 20 Ac-Nle-c (Pen-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ ID NO. ID NO: 21 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Pen) -NH2; SEQ ID NO: 21 ID NO: 22 Ac-Nle-c (Pen-D-Ala-His-D-Phe-Arg-Trp-Pen) -NH2; SEQ ID NO: 22 ID NO: 22 D-Phe-c (Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys) -Thr-NH₂; SEQ. ID NO: 23 D-Phe-c (Cys-His-D- (Et) Tyr-Arg-Trp-β-Ala-D-Cys) -Thr-NH₂; SEQ. ID NO: 24 D-Phe-c (Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys) -Thr-NH₂; SEQ. ID NO: 25 D-Phe-c (Cys-His-D- (Et) Tyr-hArg-Trp-p-Ala-D-Cys) -Thr-NH2; SEQ. ID NO: 24 D-Phe-c (Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys) -Thr-NH₂; SEQ. ID NO: 26 D-Phe-c (Cys-His-D- (Et) Tyr-hArg-Bip-β-Ala-D-Cys) -Thr-NH₂; SEQ. ID NO: 26 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys) -NH2; SEQ. ID NO: 54 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys) -NH2; SEQ. ID NO: 54 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys) -NH₂; SEQ. ID NO: 54 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 54 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys) -NH2; SEQ. ID NO: 54 Nle-c (Cys-His-D-Phe-Arg-Trp-Apn-Cys) -NH2; SEQ. ID NO: 27 Ac-Nle-c (Asp-D-Ala-His-D-Phe-Arg-Trp-Lys) -NH₂; SEQ ID NO. ID NO: 28 Ac-Nle-c (Asp-D-Ala-His-D-Phe-Arg-Bal-Lys) -NH2; SEQ. ID NO: 28 Ac-c (Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys) -NH2; SEQ. ID NO: 55 Ac-c (Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys) -NH2; SEQ. ID NO: 55 Ac-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys) -NH₂; SEQ ID NO. ID NO: 56 Ac-c (Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys) -NH2; SEQ. ID NO: 56 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys) -NH2; SEQ. ID NO: 57 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys) -NH₂; SEQ. ID NO: 57 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 57 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Pen) -OH; SEQ. ID NO: 29 Ac-Nle-c (Cys-D-Abu-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 30 Ac-Nle-c (Cys-D-Val-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ ID NO. ID NO: 30 Ac-Nle-c (Cys-D-Ile-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 30 Ac-Nle-c (Cys-D-Leu-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 30 Ac-Nle-c (Cys-D-Tle-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 30 Ac-Nle-c (Cys-D-Cha-His-D-Phe-Arg-Trp-Cys) -NH2; SEQ. ID NO: 30 Ac-Nle-c (Pen-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 31

EP 2 236 151 B1

Ac-Nle-c (Cys-His-D-Phe-Arg-Trp-Gaba-Pen) -NH2; SEQ. ID NO: 32 Ac-Nle-c (Pen-His-D-Phe-Arg-Trp-Gaba-Pen) -NH2; SEQ. ID NO: 32 Ac-Leu-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 33 Ac-Cha-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 33 Ac-Ile-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 33 Ac-Phe-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 33 Ac-Val-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 33 Ac-2-Nal-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 33 Nle-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 34 Phe-c (Cys-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 34 Ac-Nle-c (Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 35 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -OH; SEQ. ID NO: 36 Ac-Nle-c (Cys-His-Phe-Arg-D-Trp-Gaba-Cys) -NH2; SEQ. ID NO: 37 Ac-Nle-c (Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys) -NH2; SEQ. ID NO: 58 Ac-Nle-c (Asp-His-D-2-Nal-Arg-Trp-Ala-Lys) -NH2; SEQ. ID NO: 38 Ac-Nle-c (Asp-His-D-2-Nal-Arg-Trp-p-Ala-Lys) -NH₂; SEQ. ID NO: 38 Ac-Nle-c (Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys) -NH₂; SEQ. ID NO: 39 Ac-Nle-c (Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys) -NH₂; SEQ ID NO. ID NO: 39 Ac-hPhe-c (Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 40 Ac-Cha-c (Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys) -NH₂; SEQ. ID NO: 40 Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-e-Ala-Lys) -OH; SEQ. ID NO: 41 Ac-Nle-c (Cys-His-D-Phe-Arg-Trp-Ahx-Cys) -OH; SEQ. ID NO: 42 D-Phe-c (Cys-His-D-Phe-Arg-Trp-Ala-D-Cys) -Thr-OH; SEQ. ID NO: 43 D-Phe-c (Cys-His-D-Phe-Arg-Trp-p-Ala-D-Cys) -Thr-OH; SEQ. ID NO: 43 D-Phe-c (Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys) -Thr-OH; SEQ. ID NO: 43 Ac-Nle-c (Cys-His-D-Phe-Arg-Trp-Apn-Cys) -OH; SEQ. ID NO: 42 Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-Apn-Lys) -OH; SEQ. ID NO: 41 Ac-Cha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -OH; SEQ. ID NO: 44 Ac-Nle-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -OH; SEQ. ID NO: 44 Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -OH; SEQ. ID NO: 29 Ac-Chg-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -OH; SEQ. ID NO: 44 Ac-D-Cha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -OH; SEQ. ID NO: 44 Ac-hCha-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -OH; SEQ. ID NO: 44 Ac-D-Chg-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -OH; SEQ. ID NO: 44 Ac-hPhe-c (Asp-His-D-Phe-Arg-Trp-Gaba-Lys) -OH; SEQ. ID NO: 44 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys) -OH; SEQ. ID NO: 45 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys) -OH; SEQ. ID NO: 45 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-e-Ala-Cys) -OH; SEQ. ID NO: 45 Ac-Nle-c (Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys) -OH; SEQ. ID NO: 45 Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys) -OH; SEQ. ID NO: 46

EP 2 236 151 B1

Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys) -OH; SEQ. ID NO: 46

Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys) -OH; SEQ. ID NO: 46

Ac-Nle-c (Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys) -OH; SEQ. ID NO: 46

Non-Ac-c (Pen-D-Ala-His-D-Phe-Arg-Trp-Cys) -OH; SEQ. ID NO: 47

Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Pen) -OH; SEQ. ID NO: 29

Ac-Arg-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 50

Ac-D-Arg-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 50

Ac-D-Arg-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Pen) -NH₂; SEQ. ID NO: 51

Ac-D-Arg-c (Cys-His-D-Phe-Arg-Trp-Gaba-Pen) -NH₂; SEQ. ID NO: 52

Ac-Arg-c (Cys-His-D-Phe-Arg-Trp-Gaba-Pen) -NH₂; SEQ. ID NO: 52

Ac-Arg-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Pen) -NH₂; SEQ. ID NO: 51

Ac-D-Arg-c (Asp-His-D-Phe-Arg-Trp-Ala-Lys) -NH₂; SEQ. ID NO: 53

Ac-Arg-c (Asp-His-D-Phe-Arg-Trp-Ala-Lys) -NH₂; SEQ. ID NO: 53

Ac-Arg-c (Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys) -NH₂; SEQ. ID NO: 49 and

Ac-Nle-c (Cys-His-D-Phe-Arg-Trp-Gaba-Pen) -OH SEQ ID NO: ID NO: 48.

[0088] Other peptides described herein can be prepared by a person skilled in the art using synthetic methods analogous to those disclosed generally above and / or disclosed specifically in the examples, such as, for example, the compounds shown in Table 1A and 1B.

TABLES 1A and 1B - Molecular weight and purity of selected peptides [0089]

Table 1A

<td>Relationship</td><td>Calculated molecular weight</td><td>Experimental molecular weight</td><td>Cleanliness</td><td>SEQ. ID NO:</td>

<td>Ac-Nle-c (Asp-His-D-Phe-Arg-Trp0-Ala-Lys) -NH2</td><td> 1095,27</td><td> 1095,2</td><td> 96,4</td><td>SEQ. ID NO: 1</td>

<td>Ac-Nle-c (Asp-His-D-Phe-Arg-T rpA6c-Lys) -NH₂</td><td> 1149,36</td><td> 1149,05</td><td> 96</td><td>SEQ. ID NO: 1</td>

<td>Ac-Nle-c (Cys-His-D-Phe-Arg-T rpAhx-Cys) -NH₂</td><td> 1116,38</td><td> 1115,8</td><td> 98</td><td>SEQ. ID NO: 2</td>

<td>D-Phe-c (Cys-His-D-Phe-Arg-Trp-D-Cys) Thr-NH2</td><td> 1167,38</td><td> 1167,3</td><td> 99</td><td>SEQ. ID NO: 3</td>

<td>D-Phe-c (Cy s-His-D-Phe-Arg-T rpj3-Ala-D-Cys) -Thr-NH2</td><td> 1167,38</td><td> 1167,5</td><td> 93</td><td>SEQ. ID NO: 3</td>

<td>D-Phe-c (Cy s-His-D-Phe-Arg-T rpGaba-D-Cys) -Thr-NH2</td><td> 1181,41</td><td> 1181,9</td><td> 99</td><td>SEQ. ID NO: 3</td>

EP 2 236 151 B1 (continued)

<td>Relationship</td><td>Calculated molecular weight</td><td>Experimental molecular weight</td><td>Cleanliness</td><td>SEQ. ID NO:</td>

<td>Ac-Nle-c (Cys-His-D-Phe-Arg-TrpApn-Cys) -NH2</td><td> 1102,35</td><td> 1103</td><td> 99</td><td>SEQ. ID NO: 2</td>

<td>Ac-Nle-c (Asp-His-D-Phe-Arg-TrpApn-Lys) -NH2</td><td> 1123,32</td><td> 1123,9</td><td> 99</td><td>SEQ. ID NO: 4</td>

<td>Ac-A6c-c (Asp-His-D-Phe-Arg-TrpGaba-Lys) -NH2</td><td> 1121,31</td><td> 1121,2</td><td> 93</td><td>SEQ. ID NO: 5</td>

<td>Ac-D-2-Nal-c (Asp-His-D-Phe-ArgTrp-Gaba-Lys) -NH2</td><td> 1193,37</td><td> 1193,2</td><td> 92,6</td><td>SEQ. ID NO: 6</td>

<td>Ac-Cha-c (Asp-His-D-Phe-Arg-TrpGaba-Lys) -NH2;</td><td> 1149,36</td><td> 1149,4</td><td> 94,5</td><td>SEQ. ID NO: 6</td>

<td>Ac-Nle-c (Asp-His-D-Phe-Arg-TrpGaba-Lys) -NH2</td><td> 1109,3</td><td> 1109,2</td><td> 91,5</td><td>SEQ. ID NO: 6</td>

<td>Ac-Nle-c (Cys-D-Ala-His-D-PheA rg-Trp-Cy s) -NH2</td><td> 1074,3</td><td> 1074,6</td><td> 98,3</td><td>SEQ. ID NO: 7</td>

<td>Ac-Nle-c (Cys-p-Ala-His-D-PheA rg-Trp-Cy s) -NH2</td><td> 1074,3</td><td> 1074,4</td><td> 91</td><td>SEQ. ID NO: 7</td>

<td>Ac-N 1 ec (Cy sG aba - H and sD-PheArg-Trp-Cys) -NH2</td><td> 1088,32</td><td> 1088,4</td><td> 93</td><td>SEQ. ID NO: 7</td>

<td>Ac-Nle-c (Cys-Aib-His-D-PheArg-T rp-Cys) -NH?</td><td> 1088,32</td><td> 1088,4</td><td> 80</td><td>SEQ. ID NO: 7</td>

<td>Ac-Nle-c (Cys-Gly-His-D-PheArg-T rp-Cys) -N H2</td><td> 1060,27</td><td> 1060,4</td><td> 90</td><td>SEQ. ID NO: 7</td>

<td>Ac-N le-c (D-Cys-Ala-H is-DPhe-Arg-T rp-Cys) -Nł-L</td><td> 1074,3</td><td> 1074,4</td><td> 93</td><td>SEQ. ID NO: 8</td>

<td>Ac-Nle-c (D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) · -NTL</td><td> 1074,3</td><td> 1074,4</td><td> 81</td><td>SEQ. ID NO: 8</td>

<td>Ac-Nle-c (D-Cys | 3-Ala-His-D-Phe-Arg-Trp-Cys) · -NTL</td><td> 1074,3</td><td> 1074,4</td><td> 92</td><td>SEQ. ID NO: 8</td>

<td>Ac-Nle-c (D-Cys-Gaba-His-DPhe-Arg-T rp-Cys) -NEL ·</td><td> 1088,32</td><td> 1088,4</td><td> 94</td><td>SEQ. ID NO: 8</td>

<td>Ac-Nle-c (D-Cys-Aib-H is-DPhe- Arg-T rp-Cy s)-N TL·</td><td> 1088,32</td><td> 1088,4</td><td> 91</td><td>SEKW. NR ID:8</td>

<td>Ac-Nle-c(D-Cys-Gly-His-DPbe-Ar g-Trp-Cy s)-NTL·</td><td> 1060,27</td><td> 1060,4</td><td> 96</td><td>SEKW. NR ID:8</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-T rp-D-Cys)-NTL·</td><td> 1074,3</td><td> 1074,4</td><td> 66</td><td>SEKW. NR ID:9</td>

<td>Ac-N le-c(Cys-p-Ala-His-D-PheArg-T rp-D-Cys)-NTL·</td><td> 1074,3</td><td> 1074,2</td><td> 94</td><td>SEKW. NR ID:9</td>

EP 2 236 151 B1 (ciąg dalszy)

<td>Relationship</td><td>Obliczony ciężar cząsteczkowy</td><td>Eksperymentalny ciężar cząsteczkowy</td><td>Czystość</td><td>SEKW. NR ID:</td>

<td>Ac-Nle-c(Cys-Gaba-His-D-PheArg-T rp-D-Cys)-Nbk</td><td> 1088,32</td><td> 1088,2</td><td> 93</td><td>SEKW. NR ID:9</td>

<td>Ac-Nle-c(Cys-Aib-His-D-PheArg-T rp-D-Cys)-Nbk</td><td> 1088,32</td><td> 1088,4</td><td> 90</td><td>SEKW. NR ID:9</td>

<td>Ac-Nle-c(Cys-Gly-His-D-PheArg-T rp-D-Cys)-Nbk</td><td> 1060,27</td><td> 1060,4</td><td> 91</td><td>SEKW. NR ID:9</td>

<td>Ac-Nle-c(D-Cys-Ala-His-DPhe-Arg-Trp-D-Cys)-NH2</td><td> 1074,3</td><td> 1074,4</td><td> 65</td><td>SEKW. NR ID:10</td>

<td>Ac-Nle-c(D-Cys-D-Ala-His-DPhe-Arg-T rp-D-Cys)-Nbk</td><td> 1074,3</td><td> 1074,2</td><td> 93</td><td>SEKW. NR ID:10</td>

<td>Ac-Nle-c(D-Cys-(3-Ala-His-DPhe-Arg-T rp-D-Cys)-Nbk</td><td> 1074,3</td><td> 1074,4</td><td> 92</td><td>SEKW. NR ID:10</td>

<td>Ac-Nle-c(D-Cys-Gaba-His-DPhe- Arg-T rp-D-Cys)-Nbk</td><td> 1088,32</td><td> 1088,4</td><td> 90</td><td>SEKW. NR ID:10</td>

<td>Ac-Nle-c(D-Cys-Aib-His-DPhe-Arg-Trp-D-Cys)-Nbk</td><td> 1088,32</td><td> 1088</td><td> 95</td><td>SEKW. NR ID:10</td>

<td>Ac-Oic-c(Asp-His-D-Phe-ArgTrp-Gaba-Lys)-NH2</td><td> 1147,35</td><td> 1147,4</td><td> 97,5</td><td>SEKW. NR ID:11</td>

<td>Ac-Chg-c(Asp-His-D-Phe-ArgT rp-Gaba-Ly s)-N bk</td><td> 1135,33</td><td> 1135,1</td><td> 99</td><td>SEKW. NR ID:11</td>

<td>Ac-hCha-c(Asp-His-D-Phe-ArgT rg&gt;-Gaba-Lys)-N Pb</td><td> 1163,39</td><td> 1163,4</td><td> 99</td><td>SEKW. NR ID:11</td>

<td>Ac-D-Cha-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-Nbk</td><td> 1149,36</td><td> 1149,2</td><td> 99</td><td>SEKW. NR ID:11</td>

<td>Ac-Nip-c(Asp-His-D-Phe-ArgTrp-Gaba-Lys)-Nbk</td><td> 1107,28</td><td> 1107</td><td> 98,9</td><td>SEKW. NR ID:11</td>

<td>Ac-hPro-c(Asp-His-D-Phe-ArgT rp-Gaba-Lys)-N bk</td><td> 1107,28</td><td> 1107,4</td><td> 99</td><td>SEKW. NR ID:11</td>

<td>Ac-hLeu-c(Asp-His-D-Phe-ArgTrp-Gaba-Lys)-Nbk</td><td> 1123,32</td><td> 1123,2</td><td> 99</td><td>SEKW. NR ID:11</td>

<td>Ac-D-hCha-c(Asp-His-D-PheArg-T rp-Gaba-Lys)-N bk</td><td> 1163,39</td><td> 1163,6</td><td> 94</td><td>SEKW. NR ID:59</td>

<td>Ac-Phe-c( Asp-His-D-Phe-ArgT rp-Gaba-Ly s)-N bk</td><td> 1143,31</td><td> 1143,3</td><td> 96,9</td><td>SEKW. NR ID:11</td>

<td>Ac-D-Phe-c(Asp-His-D-PheArg-T rp-Gaba-Ly s)-N bk</td><td> 1143,31</td><td> 1143,3</td><td> 96,5</td><td>SEKW. NR ID:11</td>

EP 2 236 151 B1 (ciąg dalszy)

<td>Relationship</td><td>Obliczony ciężar cząsteczkowy</td><td>Eksperymentalny ciężar cząsteczkowy</td><td>Czystość</td><td>SEKW. NR ID:</td>

<td>Ac-D-Chg-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-NH2</td><td> 1135,33</td><td> 1135,4</td><td> 99</td><td>SEKW. NR ID:11</td>

<td>n-Butyryl-Cha-c(Asp-His-DPhe-Arg-T rp-Gaba-Lys)-NH2</td><td> 1177,41</td><td> 1177,5</td><td> 88,6</td><td>SEKW. NR ID:60</td>

<td>Ac-hPhe-c(Asp-His-D-Phe-ArgTrp-Gaba-Lys)-NH2</td><td> 1157,34</td><td> 1157,2</td><td> 70</td><td>SEKW. NR ID:11</td>

<td>Ac-p-hMet-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-NH2</td><td> 1141,36</td><td> 1141,2</td><td> 89</td><td>SEKW. NR ID:11</td>

<td>Ac-Gaba-c(Asp-His-D-Phe-ArgTrp-Gaba-Lys)-NH2</td><td> 1081,24</td><td> 1080,9</td><td> 92,5</td><td>SEKW. NR ID:11</td>

<td>Ac-Cha-c(Asp-His-D-Phe-ArgD-T rp-Al a-Ly s)-NH2</td><td> 1135,33</td><td> 1135,2</td><td> 85</td><td>SEKW. NR ID:13</td>

<td>Ac-hCha-c(Asp-His-D-Phe-ArgD-Trp-Ala-Lys)-NH2</td><td> 1149,36</td><td> 1149,1</td><td> 87</td><td>SEKW. NR ID:13</td>

<td>Ac-Leu-c(Asp-His-D-Phe-ArgD-Trp-Ala-Lys)-NH2</td><td> 1095,27</td><td> 1095,4</td><td> 98,6</td><td>SEKW. NR ID:13</td>

<td>Ac-hLeu-c(Asp-His-D-Phe-ArgD-Trp-Ala-Lys)-NH&gt;</td><td> 1109,3</td><td> 1109,2</td><td> 93,8</td><td>SEKW. NR ID:13</td>

<td>Ac-Phe-c(Asp-His-D-Phe-ArgD-Trp-Ala-Lys)-NH2</td><td> 1129,29</td><td> 1129,2</td><td> 81,9</td><td>SEKW. NR ID:13</td>

<td>Ac-Nle-c(Asp-His-D-Phe-ArgD-Trp-D-Ala-Lys)-NH2</td><td> 1095,27</td><td> 1095,3</td><td> 97</td><td>SEKW. NR ID:14</td>

<td>Ac-Nle-c(Asp-His-D-Phe-ArgD-Trp-p-Ala-Lys)-NH2</td><td> 1095,27</td><td> 1095,3</td><td> 82</td><td>SEKW. NR ID:14</td>

<td>Ac-Nle-c(Asp-His-D-Phe-ArgD-Trp-Gaba-Lys)-NH2</td><td> 1109,3</td><td> 1109,1</td><td> 99</td><td>SEKW. NR ID:14</td>

<td>Ac-Nle-c(Asp-His-D-Phe-ArgD-Trp-Aha-Lys)-NH2</td><td> 1137,35</td><td> 1137,4</td><td> 98</td><td>SEKW. NR ID:14</td>

<td>Ac-Nle-c(Asp-His-D-Phe-ArgD-T rp-Apn-Lys)-NJ-L·</td><td> 1123,32</td><td> 1123,3</td><td> 97,3</td><td>SEKW. NR ID:14</td>

<td>Ac-Nle-c(Cys-His-D-Phe-ArgD-T rp-Apn-Cys)-NH2</td><td> 1102,35</td><td> 1102</td><td> 99</td><td>SEKW. NR ID:15</td>

<td>Ac-Nle-c(Cys-His-D-Phe-ArgD-Trp-Gaba-Cys)-NH&gt;</td><td> 1088,32</td><td> 1087,8</td><td> 97</td><td>SEKW. NR ID:15</td>

<td>Ac-Nle-c(Cys-His-D-Phe-ArgD-T rp-Ahx-Cys)-NH2</td><td> 1116,38</td><td> 1116,2</td><td> 99</td><td>SEKW. NR ID:15</td>

EP 2 236 151 B1 (ciąg dalszy)

<td>Relationship</td><td>Obliczony ciężar cząsteczkowy</td><td>Eksperymentalny ciężar cząsteczkowy</td><td>Czystość</td><td>SEKW. NR ID:</td>

<td>Ac-Nle-c(Cys-His-D-Phe-ArgD-T rp-)3-Ala-Cys)-NH2</td><td> 1074,3</td><td> 1073,8</td><td> 99,9</td><td>SEKW. NR ID:15</td>

<td>Ac-Nle-c(Cys-His-D-Phe-ArgD-Trp-D-Ala-Cys)-NH2</td><td> 1074,3</td><td> 1073,8</td><td> 99,9</td><td>SEKW. NR ID:15</td>

<td>Ac-Nle-c(Cys-D-Ala-His-D-2Nal-Arg-Trp-Cys)-NH2</td><td> 1124,36</td><td> 1123,6</td><td> 96,1</td><td>SEKW. NR ID:16</td>

<td>Ac-Nle-c(Cys-D-Ala-His-D-2Nal-Arg-2-Nal-Cys)-NH2</td><td> 1135,38</td><td> 1134,5</td><td> 99,1</td><td>SEKW. NR ID:16</td>

<td>Ac-Nle-c(Cys-D-Ala-His-D-2Nal-Arg-1-Nal-Cys)-NH2</td><td> 1135,38</td><td> 1134,6</td><td> 94,8</td><td>SEKW. NR ID:16</td>

<td>nButanoyl-Nle-c(Cys-D-AlaHis-D-Phe-Arg-2-Nal-Cys)-NPh</td><td> 1113,37</td><td> 1112,6</td><td> 95,7</td><td>SEKW. NR ID:17</td>

<td>nButanoyl-Nle-c(Cys-D-AlaHis-D-Phe-Arg-T rp-Cys)-NH&gt;</td><td> 1102,35</td><td> 1101,5</td><td> 99,9</td><td>SEKW. NR ID:17</td>

<td>Ac-N 1 e-c( Cy s-D-Al a-H i s-DPhe-Arg-2-Nal-Cys)-Nł-h</td><td> 1085,32</td><td> 1084,4</td><td> 97,7</td><td>SEKW. NR ID:18</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-1-Nal-Cys)-NH&gt;</td><td> 1085,32</td><td> 1084,5</td><td> 96,6</td><td>SEKW. NR ID:18</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-Bal-Cys)-NH2</td><td> 1091,35</td><td> 1090,4</td><td> 96,2</td><td>SEKW. NR ID:18</td>

<td>Ac-Nle-c(Cys-D-Glu-His-DPhe-Arg-Trp-Cys)-NH2</td><td> 1132,33</td><td> 1131,5</td><td> 99,9</td><td>SEKW. NR ID:61</td>

<td>Ac-Nle-c(Asp-His-D-Phe-ArgTrp-D-Ala-Lys)-NH&gt;</td><td> 1095,27</td><td> 1094,6</td><td> 99,9</td><td>SEKW. NR ID:19</td>

<td>Ac-Nle-c(Cys-D-Ala-His-D-2Nal-Arg-Bal-Cys)-NH&gt;</td><td> 1141,41</td><td> 1140,5</td><td> 95,6</td><td>SEKW. NR ID:20</td>

<td>Ac-Nle-c(Pen-D-Ala-His-DPhe-Arg-Trp-Cys)-NH2</td><td> 1102,35</td><td> 1101,6</td><td> 99,9</td><td>SEKW. NR ID:21</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-Trp-Pen)-NH2</td><td> 1102,35</td><td> 1101,6</td><td> 99,9</td><td>SEKW. NR ID:22</td>

<td>Ac-Nle-c(Pen-D-Al a-His-DPhe-Arg-T rp-Pen )-NH?</td><td> 1130,4</td><td> 1129,6</td><td> 99,9</td><td>SEKW. NR ID:22</td>

<td>D-Phe-c(Cys-His-D-Phe-hArgTrp-[3-Ala-D-Cys)-Thr-NH2</td><td> 1181,41</td><td> 1181,7</td><td> 96,9</td><td>SEKW. NR ID:23</td>

EP 2 236 151 B1 (ciąg dalszy)

<td>Relationship</td><td>Calculated molecular weight</td><td>Experimental molecular weight</td><td>Czystość</td><td>SEKW. NR ID:</td>

<td>D-Phe-c(Cys-His-D-(Et)T yrArg-T rp-|3-A1 a -D-Cy s)-Th r- NEL·</td><td> 1211,43</td><td> 1211,7</td><td> 97,1</td><td>SEKW. NR ID:24</td>

<td>D-Phe-c(Cys-His-D-Phe-ArgBi ρ-β-Ala-D-Cy s)-Thr-N EL·</td><td> 1204,44</td><td> 1204,6</td><td> 99</td><td>SEKW. NR ID:25</td>

<td>D-Phe-c(Cys-His-D-(Et)Tyr-hArgTrp-p-Ala-D-Cys)-Thr-NH₂</td><td> 1225,46</td><td> 1225,7</td><td> 97</td><td>SEKW. NR ID:24</td>

<td>D-Phe-c(Cys-His-D-Phe-hArgBip&gt;-f3-Ala-D-Cys)-Thr-NEh</td><td> 1218,47</td><td> 1218,8</td><td> 99</td><td>SEKW. NR ID:26</td>

<td>D-Phe-c(Cys-His-D-(Et)Tyr-hArgBip-p-Ala-D-Cys)-Thr-Nl-L·</td><td> 1262,52</td><td> 1263</td><td> 99</td><td>SEKW. NR ID:26</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-Trp-Gly-Cys)-NEL·</td><td> 1131,35</td><td> 1131,2</td><td> 96,8</td><td>SEKW. NR ID:54</td>

<td>Ac-N le-c(Cys-D-Ala-EIis-DPhe-Arg-Trp-D-Ala-Cys)-NEL·</td><td> 1145,37</td><td> 1145,3</td><td> 96,4</td><td>SEKW. NR ID:54</td>

<td>Ac-N le-c(Cys-D-Ala-His-DPhe-Arg-Trp-p-Ala-Cys)-NH2</td><td> 1145,37</td><td> 1145,2</td><td> 98,2</td><td>SEKW. NR ID:54</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-Trp-Gaba-Cys)-NEL·</td><td> 1159,4</td><td> 1159,2</td><td> 95,1</td><td>SEKW. NR ID:54</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-Trp-Apn-Cys)-NEL·</td><td> 1173,43</td><td> 1173,3</td><td> 96,8</td><td>SEKW. NR ID:54</td>

<td>Nle-c(Cys-His-D-Phe-Arg-TrpApn-Cys)-NEL·</td><td> 1060,31</td><td> 1060,3</td><td> 98,5</td><td>SEKW. NR ID:27</td>

<td>Ac-Nle-c(Asp-D-Ala-His-DPhe-Arg-Trp-Lys)-NEL·</td><td> 1095,27</td><td> 1094,7</td><td> 96,2</td><td>SEKW. NR ID:28</td>

<td>Ac-N le-c( Asp-D-Ala-His-DPhe-Arg-Bal-Lys)-NEL·</td><td> 1112,32</td><td> 1111,7</td><td> 96,5</td><td>SEKW. NR ID:28</td>

<td>Ac-c(Cys-Glu-His-D-Phe-ArgT rp-Al a-Cy s)-NEL·</td><td> 1090,25</td><td> 1089,6</td><td> 99,9</td><td>SEKW. NR ID:55</td>

<td>Ac-c(Cy s-G lu -H is-D-Phe-Arg-2Nal-Ala-Cys)-NEL·</td><td> 1101,27</td><td> 1100,6</td><td> 98,3</td><td>SEKW. NR ID:55</td>

<td>Ac-c(Cys-D-Ala-His-D-PheArg-Trp-Ala-Cys)-NEL·</td><td> 1032,22</td><td> 1031,5</td><td> 95,2</td><td>SEKW. NR ID:56</td>

<td>Ac-c(Cys-D-Ala-His-D-PheArg-2-Nal-Ala-Cys)-NEL·</td><td> 1043,24</td><td> 1042,5</td><td> 95,6</td><td>SEKW. NR ID:56</td>

EP 2 236 151 B1 (ciąg dalszy)

<td>Relationship</td><td>Calculated molecular weight</td><td>Experimental molecular weight</td><td>Cleanliness</td><td>SEQ. ID NO:</td>

<td>Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cysj-Nbk</td><td> 1144,39</td><td> 1144,6</td><td> 95,3</td><td>SEQ. ID NO: 57</td>

<td>Ac-Nle-c (Cys-D-AJa-His-DPhe-Arg-T rp-p-Ala-Cysj-NH?</td><td> 1145,37</td><td> 1144,6</td><td> 97,3</td><td>SEQ. ID NO: 57</td>

<td>Ac-Nle-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys) -NH2</td><td> 1158,41</td><td> 1158,6</td><td> 96,5</td><td>SEQ. ID NO: 57</td>

<td>Ac-Nle-c (Cys-D-Ala-His-DP he-A rg-Trp-Pen) -O H</td><td> 1103,33</td><td> 1103</td><td> 99,9</td><td>SEQ. ID NO: 29</td>

<td>Ac-Nle-c (Cys-D-Abu-His-D-Phe-Arg-Trp-Cys) -Nbh</td><td> 1088,32</td><td> 1087,6</td><td> 99,9</td><td>SEQ. ID NO: 30</td>

<td>Ac-Nle-c (Cys-D-Val-His-D-PheArg-T rp-Cys) -Nbh</td><td> 1102,35</td><td> 1101,7</td><td> 99,9</td><td>SEQ. ID NO: 30</td>

<td>Ac-Nle-c (Cys-D-Ile-His-D-PheArg-T rp-Cys) -N bh</td><td> 1116,38</td><td> 1115,7</td><td> 99,9</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Cys-D-Leu-His-DPhe-Arg-T r p-Cy s)-N bh</td><td> 1116,38</td><td> 1115,8</td><td> 97,4</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Cys-D-Tle-His-D-PheArg-Trp-Cys)-Nbh</td><td> 1116,38</td><td> 1115,5</td><td> 96,5</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Cys-D-Cha-His-DPhe-Arg-T rp-Cy s)-Nbh</td><td> 1156,44</td><td> 1155,6</td><td> 96,4</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Pen-His-D-Phe-ArgT rp-Gaba-Cy s)-N hb</td><td> 1116,38</td><td> 1115,7</td><td> 95</td><td>SEKW. NR ID:31</td>

<td>Ac-N 1 e-c( Cy s-H is-D-Phe-ArgTrp-Gaba-Pen)-NH2</td><td> 1116,38</td><td> 1115,5</td><td> 99,9</td><td>SEKW. NR ID:32</td>

<td>Ac-N le-c(Pen-His-D-Phe- ArgTrp-Gaba-Pen)-NH2</td><td> 1144,43</td><td> 1144</td><td> 99,9</td><td>SEKW. NR ID:32</td>

<td>Ac-Leu-c(Cys-His-D-Phe-ArgTrp-Gaba-Cys)-Nbh</td><td> 1088,32</td><td> 1088</td><td> 96,7</td><td>SEKW. NR ID:33</td>

<td>Ac-Cha-c(Cys-His-D-Phe-ArgTrp-Gaba-Cys)-Nhh</td><td> 1128,39</td><td> 1128,4</td><td> 95,8</td><td>SEKW. NR ID:33</td>

<td>Ac-I le-c(Cys-His-D-Phe- ArgTrp-Gaba-Cys)-NH2</td><td> 1088,32</td><td> 1088,4</td><td> 95</td><td>SEKW. NR ID:33</td>

<td>Ac-Phe-c(Cys-His-D-Phe-ArgTrp-Gaba-Cys)-NH2</td><td> 1122,34</td><td> 1122</td><td> 95,2</td><td>SEKW. NR ID:33</td>

<td>Ac-Val-c(Cys-His-D-Phe-ArgTrp-Gaba-Cys)-Nhh</td><td> 1074,3</td><td> 1074,6</td><td> 95,4</td><td>SEKW. NR ID:33</td>

EP 2 236 151 B1 (ciąg dalszy)

<td>Relationship</td><td>Calculated molecular weight</td><td>Experimental molecular weight</td><td>Czystość</td><td>SEKW. NR ID:</td>

<td>Ac-2-Nal-c(Cys-His-D-Phe-ArgT rp-Gaba-Cys)-NH2</td><td> 1172,4</td><td> 1172,2</td><td> 95,2</td><td>SEKW. NR ID:33</td>

<td>Nle-c(Cys-His-D-Phe-Arg-TrpGaba-Cys)-NH2</td><td> 1046,29</td><td> 1046,4</td><td> 97,6</td><td>SEKW. NR ID:34</td>

<td>Phe-c(Cys-His-D-Phe-Arg-TrpGaba-Cys)-NH2</td><td> 1080,3</td><td> 1080</td><td> 95,8</td><td>SEKW. NR ID:34</td>

<td>Ac-Nle-c(Cys-3-Pal-D-Phe-ArgTrp-Gaba-Cys)-NPL·</td><td> 1099,35</td><td> 1099,6</td><td> 96,6</td><td>SEKW. NR ID:35</td>

<td>Ac-N 1 e-c( Cy s-D-Ala-H is-DPhe-Arg-T rp-Cys)-OH</td><td> 1075,28</td><td> 1075,2</td><td> 99,9</td><td>SEKW. NR ID:36</td>

<td>Ac-Nle-c(Cy s-His-Phe-Arg-DTrp-Gaba-Cys)-NI-h</td><td> 1088,32</td><td> 1088</td><td> 95,8</td><td>SEKW. NR ID:37</td>

<td>Ac-Nle-c(Asp-D-Ala-His-D-PheArg-Bal-Ala-Lys)-NH2</td><td> 1183,4</td><td> 1182,85</td><td> 99,9</td><td>SEKW. NR ID:58</td>

<td>Ac-Nle-c(Asp-His-D-2-Nal-ArgT rp-Ala-Ly s)-NH2</td><td> 1145,33</td><td> 1145</td><td> 99,99</td><td>SEKW. NR ID:38</td>

<td>Ac-Nle-c(Asp-His-D-2-N al-ArgTrp-PAla-Lys)-NH2</td><td> 1145,33</td><td> 1145</td><td> 99,99</td><td>SEKW. NR ID:38</td>

<td>Ac-Nle-c(Cy s-His-D-2-Ν al-ArgT rp-Gaba-Cys)-NH2</td><td> 1138,38</td><td> 1137,8</td><td> 99,99</td><td>SEKW. NR ID:39</td>

<td>Ac-Nle-c(Cys-His-D-2-Nal-ArgTrp-Ahx-Cys)-NH2</td><td> 1166,44</td><td> 1166</td><td> 99</td><td>SEKW. NR ID:39</td>

<td>Ac-hPhe-c(Asp-His-D-2-Nal-ArgTrp-Gaba-Lys)-NH2</td><td> 1207,4</td><td> 1206,9</td><td> 99</td><td>SEKW. NR ID:40</td>

<td>Ac-Cha-c( Asp-His-D-2-Ν al-ArgT rp-Gaba-Ly s)-NH2</td><td> 1199,42</td><td> 1198,8</td><td> 100</td><td>SEKW. NR ID:40</td>

<td>Ac-Arg-c(Cys-D-Ala-His-D-PheArg-Trp-Cys)-NH2</td><td> 1117,3</td><td> 1116,9</td><td> 95,10</td><td>SEKW. NR ID:50</td>

<td>Ac-D-Arg-c(Cys-D-Ala-His-D-PheA rg-Trp-Cy s)-NH2</td><td> 1117,33</td><td> 1116,8</td><td> 99,2</td><td>SEKW. NR ID:50</td>

<td>Ac-D-Arg-c(Cys-D-Ala-His-D-PheA rg-T rp-Pen)-NH2</td><td> 1145,38</td><td> 1144,9</td><td> 96,4</td><td>SEKW. NR ID:51</td>

<td>Ac-D-Arg-c(Cys-His-D-Phe-ArgT rp-Gaba-Pen)-NH2</td><td> 1159,41</td><td> 1158,9</td><td> 99,9</td><td>SEKW. NR ID:52</td>

<td>Ac-Arg-c(Cys-His-D-Phe-Arg-TrpGaba-Pen)-NH2</td><td> 1159,41</td><td> 1159,1</td><td> 99</td><td>SEKW. NR ID:52</td>

<td>Ac-Arg-c(Cys-D-Ala-His-D-PheArg-Trp-Pen)-NH2</td><td> 1145,38</td><td> 1145,1</td><td> 99</td><td>SEKW. NR ID:51</td>

EP 2 236 151 B1 (ci further)

<td>Relationship</td><td>Calculated molecular weight</td><td>Experimental molecular weight</td><td>Cleanliness</td><td>SEQ. ID NO:</td>

<td>Ac-D-Arg-c (Asp-His-D-Phe-ArgTrp-Ala-Lys) -NH2</td><td> 1138,3</td><td> 1138,0</td><td> 98,0</td><td>SEQ. ID NO: 53</td>

<td>Ac-Arg-c (Asp-His-D-Phe-Arg-Trp-Lys) -NH2</td><td> 1138,3</td><td> 1138,1</td><td> 99,0</td><td>SEQ. ID NO: 53</td>

Table 1B

<td>Relationship</td><td>Calculated molecular weight</td><td>Experimental molecular weight</td><td>Cleanliness</td><td>SEQ. ID NO:</td>

<td>Ac-Arg-c (Cys-D-Ala-His-D-2-NalArg-T rp-Cy s) -NH2</td><td> 1167,39</td><td> 1167,40</td><td> 99,9</td><td>SEQ. ID NO: 49</td>

Example 3: In vitro studies [0090] The compounds described herein can be tested and tested for ligand activity of one or more melanocortin receptors according to the following procedures. It will be apparent to those skilled in the art that procedures similar to those described herein can be used to test the binding activity of compounds with m-elanocortin receptor molecules.

Radioligand binding assays [0091] Cell membranes used for in vitro receptor binding assays were obtained from transgenic CHO-K1 cells stably expressing hMC-R receptor 1, 3, 4 or 5 subtypes. CHO-K1 cells expressing the desired hMC-R receptor type were sonicated (Branson® regulation 7, about 30 seconds) in ice-cold 50 mM Tris-HCl at pH 7.4, followed by centrifugation at 39,000 g for 10 minutes at about 4 ° C. The pellets were resuspended in the same buffer and centrifuged at 50,000 g for 10 minutes at a temperature of about 4 ° C. Washed pellets containing cell membranes were stored at about -80 ° C.

[0092] Competitive binding inhibition [¹²⁵I] (Tyr²) - (Nle⁴-D-Phe⁷) a-MSH ([¹²⁵I] -NDP-a-MSH, Amersham Biosciences®) was run on 96 well polypropylene plates. Cell membranes prepared as described above (1-10 pg protein / well) were incubated in 50 mM Tris-HCl at pH 7.4 containing 0.2% fetal bovine serum (BSA), 5 mM MgCl₂, 1 mM CaCl₂ and 0.1 mg / ml bacitracin, along with increasing concentrations of test compound and 0.1-0.3 nM [¹²⁵I] -NDP-a-MSH for about 90-120 minutes at a temperature of about 37 ° C. Bound ligand [¹²⁵I] -NDP-a-MSH was separated from the free [¹²⁵I] -NDP-a-MSH by filtration through GF / C glass fiber filter plates (Unifilter®; Packard), previously rinsed with 0.1% (w / v) polyethyleneimine (PEI) using a Packard Filtermate® harvester . The filters were washed three times with 50 mM Tris-HCl at pH 7.4 at a temperature of about 0-4 ° C, and then radioactivity was tested,

EP 2 236 151 B1 using a Packard Topcount® scintillation counter. Data for binding were analyzed using computer aided non-linear regression analysis (XL fit; IDBS).

[0093] Selected peptides were tested in the test described above, and binding constants (Ki in nM) are shown in Tables 2A, 2B and 2C.

TABLES 2A, 2B and 2C - Data from the radioligand binding study for selected compounds [0094]

Table 2A

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R / MC4-R</td><td>SEQ. ID NO:</td>

<td>Ac-Arg-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) -NH2</td><td> 3,87</td><td> 10,1</td><td> 2,09</td><td> 430</td><td> 1,9</td><td>SEQ. ID NO: 50</td>

<td>Ac-D-Arg-c (Cys-D-Ala-HisD-Phe-Arg-T rp-Cys) -N Hi</td><td> 4,01</td><td> 12,1</td><td> 1,76</td><td> 352</td><td> 2,3</td><td>SEQ. ID NO: 50</td>

<td>Ac-D-Arg-c (Cys-D-Ala-HisD-Phe-Arg-Trp-Penj-NHI</td><td> 8,29</td><td> 13,3</td><td> 2,78</td><td> 816</td><td> 3,0</td><td>SEQ. ID NO: 51</td>

<td>Ac-D-Arg-c (Cys-His-D-PheArg-Trp-Gaba-Pen) -NH2</td><td> 3,93</td><td> 172</td><td> 11,0</td><td> 538</td><td> 0,36</td><td>SEQ. ID NO: 52</td>

<td>Ac-Arg-c (Cys-His-D-PheArg-T rp-Gaba-Pen) -NH2</td><td> 1,81</td><td> 20,5</td><td> 4,57</td><td> 502</td><td> 0,4</td><td>SEQ. ID NO: 52</td>

<td>Ac-Arg-c (Cys-D-Ala-His-D-Phe-Arg-Trp-Pen) -NH2</td><td> 9,67</td><td> 22,0</td><td> 4,2</td><td> 1900</td><td> 2,3</td><td>SEQ. ID NO: 51</td>

<td>Ac-D-Arg-c (Asp-His-DPhe-Arg-T rp- Ala-Lys) -NJ-Ł&gt;</td><td> 0,79</td><td> 45,5</td><td> 1,21</td><td> 493</td><td> 0,6</td><td>SEKW. NR ID:53</td>

<td>Ac-Arg-c(Asp-His-D-PheArg-Trp-Ala-Lys)-NH&gt;</td><td> 0,68</td><td> 20,7</td><td> 1,01</td><td> 783</td><td> 0,7</td><td>SEKW. NR ID:53</td>

Tablica 2B

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-Nle-c(Cys-D-Ala-His-D2-Nal-Arg-l -NaJ-Cysj-NH?</td><td> 114</td><td> 63,9</td><td> 3,07</td><td> 1657</td><td> 37,1</td><td>SEKW. NR ID:16</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-T rp-Cy s)-N Hi</td><td> 11</td><td> 26</td><td> 7,6</td><td> 1800</td><td> 1,4</td><td>SEKW. NR ID:7</td>

<td>D-Phe-c(Cys-His-D-(Et)TyrArg-Trp^-Ala-D-Cys)-ThrNH2</td><td> 0,05</td><td> 9,3</td><td> 1,1</td><td> 2,9</td><td> 0,0</td><td>SEKW. NR ID:24</td>

EP 2 236 151 B1

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Nle-c(Cys-His-D-Phe-ArgTrp-Apn-Cys)-NH2</td><td> 0,07</td><td> 4,1</td><td> 0,85</td><td> 8,8</td><td> 0,1</td><td>SEKW. NR ID:27</td>

<td>Ac-Nle-c(Cys-His-D-PheArg-Trp-Gaba-Pen)-NH2</td><td> 0,12</td><td> 10</td><td> 0,43</td><td> 0,42</td><td> 0,3</td><td>SEKW. NR ID:32</td>

<td>ΝI e-c(Cy s-H i s-D-Phe-ArgT rp-Gaba-Cy s)-NH2</td><td> 0,05</td><td> 1,3</td><td> 0,47</td><td> 0,2</td><td> 0,1</td><td>SEKW. NR ID:34</td>

<td>Ac-Nle-c(Asp-His-D-PheArg-T rp-β-Ala-Lys)-N Hz</td><td> 0,0996</td><td> 9318</td><td> 0,617</td><td> 10,9</td><td> 0,16</td><td>SEKW. NR ID:1</td>

<td>Ac-Nle-c(Cys-His-D-PheArg-T rp-Ahx-Cys)-NH&gt;</td><td> ,0132</td><td> 16,1</td><td> 1,23</td><td> 0,359</td><td> 0,11</td><td>SEKW. NR ID:2</td>

<td>D-Phe-c(Cys-His-D-Phe-ArgTrp-P-Ala-D-Cys)-Thr-NH2</td><td> 0,207</td><td> 43,2</td><td> 2,58</td><td> 344</td><td> 0,08</td><td>SEKW. NR ID:3</td>

<td>D-Phe-c(Cys-H is-D- Phe-A rgT rp-Gaba-D-Cy s)-Th r-N H2</td><td> 0,420</td><td> 106</td><td> 4,75</td><td> 1260</td><td> 0,09</td><td>SEKW. NR ID:3</td>

<td>Ac-Nle-c(Cys-His-D-PheArg-Trp-Apn-Cys)-NH2</td><td> 0,0951</td><td> 9,33</td><td> 0,894</td><td> 13,4</td><td> 0,11</td><td>SEKW. NR ID:2</td>

<td>Ac-Nle-c(Asp&gt;-His-D-PheArg-Trp-Apn-Lys)-NH2</td><td> 0,999</td><td> 300</td><td> 11,1</td><td> 431</td><td> 0,09</td><td>SEKW. NR ID:4</td>

<td>Ac-Cha-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-NPh</td><td> 0,106</td><td> 11,8</td><td> 1,49</td><td> 110</td><td> 0,07</td><td>SEKW. NR ID:6</td>

<td>Ac-Nle-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-NH&gt;</td><td> 0,0506</td><td> 9,89</td><td> 1,04</td><td> 16,3</td><td> 0,05</td><td>SEKW. NR ID:6</td>

<td>Ac-Chg-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-NH&gt;</td><td> 0,884</td><td> 223</td><td> 22,5</td><td> 609</td><td> 0,04</td><td>SEKW. NR ID:11</td>

<td>Ac-hCha-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-NH2</td><td> 0,721</td><td> 93,5</td><td> 56,0</td><td> 747</td><td> 0,01</td><td>SEKW. NR ID:11</td>

<td>Ac-D-Chg-c(Asp-His-D-PheArg-Trp-Gaba-Lys)-NH2</td><td> 0,227</td><td> 14,5</td><td> 2,99</td><td> 164</td><td> 0,08</td><td>SEKW. NR ID:11</td>

<td>Ac-hPhe-c(Asp-His-D-PheArg-Trp&gt;-Gaba-Lys)-NH2</td><td> 0,277</td><td> 25,2</td><td> 3,37</td><td> 203</td><td> 0,08</td><td>SEKW. NR ID:11</td>

<td>Ac-N le-c(Cy s-His-D-PheArg-D-Trp-P-Ala-Cys)-NH2</td><td> 0,323</td><td> 14,1</td><td> 1,96</td><td> 24,0</td><td> 0,16</td><td>SEKW. NR ID:15</td>

EP 2 236 151 B1

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-N le-c (Pen -D-A1 a-H i s-DPhe-Arg-T rp-Cy s)-NHi</td><td> 34,1</td><td> 118</td><td> 17,0</td><td> 5560</td><td> 2,01</td><td>SEKW. NR ID:21</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-T rp-Pen )-NTh</td><td> 29,1</td><td> 22,8</td><td> 3,84</td><td> 2550</td><td> 7,58</td><td>SEKW. NR ID:22</td>

<td>D-Phe-c(Cys-His-D-Phe-hArgTrp-p-Ala-D-Cys)-Thr-NH₂</td><td> 0,442</td><td> 123</td><td> 10,3</td><td> 521</td><td> 0,04</td><td>SEKW. NR ID:23</td>

<td>D-Phe-c(Cys-His-D-Phe-ArgBip-P-Ala-D-Cys)-Thr-NH2</td><td> 5,80</td><td> 3370</td><td> 583</td><td> 1130</td><td> 0,01</td><td>SEKW. NR ID:25</td>

<td>D-Phe-c(Cys- H is-D-( Et)Ty rhArg-Trp-p-Ala-D-Cys)-ThrNH₂</td><td> 0,0567</td><td> 31,4</td><td> 14,7</td><td> 9,27</td><td> 0</td><td>SEKW. NR ID:24</td>

<td>D-Phe-c(Cys- H is-D-Phe-h ArgBip-p-Ala-D-Cys)-Thr-NH2</td><td> 1,68</td><td> 1260</td><td> 172</td><td> 1220</td><td> 0,01</td><td>SEKW. NR ID:26</td>

<td>D- Phe-c(Cys-H is- D-(Et)T y rhArg-Bip-P-Ala-D-Cys)-ThrNH2</td><td> 0,128</td><td> 85,6</td><td> 36,9</td><td> 38,0</td><td> 0</td><td>SEKW. NR ID:26</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-T rp-G 1 y-Cy s)-NH2</td><td> 0,352</td><td> 149</td><td> 3,01</td><td> 339</td><td> 0,12</td><td>SEKW. NR ID:54</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-Trp-D-Ala-Cys)-NH2</td><td> 3,93</td><td> 876</td><td> 48,0</td><td> 4940</td><td> 0,08</td><td>SEKW. NR ID:54</td>

<td>Ac-Nle-c(Cy s-D-Ala-H is-DPbe-Arg-Trp-β-Al a -Cys )NEL</td><td> 0,995</td><td> 287</td><td> 4,80</td><td> 766</td><td> 0,21</td><td>SEKW. NR ID:54</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-A rg-T rp-Gaba-Cy s)-N H2</td><td> 0,848</td><td> 184</td><td> 3,76</td><td> 956</td><td> 0,23</td><td>SEKW. NR ID:54</td>

<td>Ac-N le-c(Cys-D-Ala-His-DPhe- A rg-T rp-A pn -Cys)- Ν H2</td><td> 1,10</td><td> 228</td><td> 7,58</td><td> 859</td><td> 0,15</td><td>SEKW. NR ID:54</td>

<td>Ac-N le-c( Asf&gt;-D-Al a-H is-DPhe-Arg-Trp-Lys)-NH2</td><td> 0,659</td><td> 98,9</td><td> 2,55</td><td> 4,19</td><td> 0,26</td><td>SEKW. NR ID:28</td>

<td>Ac-Nle-c(Asp-D-Ala-His-DPhe-Arg-Bal-Lys)-NH2</td><td> 4,12</td><td> 445</td><td> 50,6</td><td> 4300</td><td> 0,08</td><td>SEKW. NR ID:28</td>

<td>Ac-c(Cys-Glu-His-D-PheArg-Trp-Ala-Cys)-NTk</td><td> 111</td><td> 1710</td><td> 47,7</td><td> 694</td><td> 2,33</td><td>SEKW. NR ID:55</td>

EP 2 236 151 B1

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-c(Cys-Glu-His-D-PheArg-2-Nal-Ala-Cys)-NH2</td><td> 262</td><td> 2500</td><td> 96,4</td><td> 1460</td><td> 2,72</td><td>SEKW. NR ID:55</td>

<td>Ac-c(Cys-D-Ala-His-D-PheArg-Trp-Ala-Cys)-NH2</td><td> 199</td><td> 5990</td><td> 96,7</td><td> &gt;10000</td><td> 2,06</td><td>SEKW. NR ID:56</td>

<td>Ac-c(Cys-D-Ala-His-D-PheArg-2-Nal-Ala-Cys)-NH2</td><td> 132</td><td> 4560</td><td> 40,7</td><td> 8810</td><td> 3,24</td><td>SEKW. NR ID:56</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-A rg-T r p-Ala-Cy s)-N H&gt;</td><td> 9,12</td><td> 1130</td><td> 22,1</td><td> 2860</td><td> 0,41</td><td>SEKW. NR ID:57</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-Trp-P-Ala-Cys)-NH2</td><td> 1,00</td><td> 227</td><td> 5,55</td><td> 496</td><td> 0,18</td><td>SEKW. NR ID:57</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-A rg-Trp-Gaba-Cy s)-N H2</td><td> 0,536</td><td> 169</td><td> 3,12</td><td> 358</td><td> 0,17</td><td>SEKW. NR ID:57</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-T rp-Pen )-OH</td><td> 32,1</td><td> 330</td><td> 17,4</td><td> 165</td><td> 1,84</td><td>SEKW. NR ID:29</td>

<td>Ac-Nle-c(Cys-D-Abu-HisD-Phe-Arg-Trp-Cys)-NH2</td><td> 10,6</td><td> 41,1</td><td> 7,69</td><td> 54,9</td><td> 1,38</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Cys-D-Val-His-DPhe-Arg-T rp-Cy s)-NH2</td><td> 13,0</td><td> 104</td><td> 10,1</td><td> 40</td><td> 1,29</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Cys-D-Ile-His-DPhe-Arg-T rp-Cys)-NH2</td><td> 4,28</td><td> 38,5</td><td> 9,0</td><td> 12,5</td><td> 0,48</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Cys-D-Leu-His-DPhe-Arg-Trp-Cys)-NH2</td><td> 1,60</td><td> 6,82</td><td> 4,13</td><td> 5,57</td><td> 0,39</td><td>SEKW. NR ID:30</td>

<td>Ac-N le-c(Cys-D-Tle-His-DPhe-Arg-Trp-Cys)-NH2</td><td> 12,0</td><td> 85,8</td><td> 11,2</td><td> 40</td><td> 1,07</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Cys-D-Cha-His-DPhe-Arg-T rp-Cy s)-N hb</td><td> 0,353</td><td> 2,08</td><td> 1,41</td><td> 0,857</td><td> 0,25</td><td>SEKW. NR ID:30</td>

<td>Ac-Nle-c(Pen-His-D-PheArg-T rp-Gaba -Cy s)-NH&gt;</td><td> 0,537</td><td> 86,1</td><td> 5,89</td><td> 2,56</td><td> 0,09</td><td>SEKW. NR ID:31</td>

<td>Ac-Nle-c(Pen-His-D-PheArg-Trp-Gaba-Pen)-NH2</td><td> 0,744</td><td> 178</td><td> 3,51</td><td> 2,69</td><td> 0,21</td><td>SEKW. NR ID:32</td>

<td>Ac-Leu-c(Cys-His-D-PheArg-Trp-Gaba-Cys)-NH2</td><td> 0,216</td><td> 17,4</td><td> 0,995</td><td> 0,486</td><td> 0,22</td><td>SEKW. NR ID:33</td>

EP 2 236 151 B1

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-Cha-c(Cys-His-D-PheArg-Trp-Gaba-Cys)-NH2</td><td> 0,107</td><td> 9,11</td><td> 0,884</td><td> 0,354</td><td> 0,12</td><td>SEKW. NR ID:33</td>

<td>Ac-I le-c(Cys-Hi s-D-PheArg-T rp-Gaba-Cys)-N Pb</td><td> 0,148</td><td> 13,9</td><td> 1,06</td><td> 0,423</td><td> 0,14</td><td>SEKW. NR ID:33</td>

<td>Ac-Phe-c(Cys-His-D-PheArg-Trp-Gaba-Cys)-NH2</td><td> 0,254</td><td> 18,5</td><td> 2,13</td><td> 0,714</td><td> 0,12</td><td>SEKW. NR ID:33</td>

<td>Ac-Val-c(Cys-His-D-PheArg-T rp-Gaba-Cy s)-N Hi</td><td> 0,256</td><td> 29,9</td><td> 1,98</td><td> 0,864</td><td> 0,13</td><td>SEKW. NR ID:33</td>

<td>Ac-2-Nal-c(Cys-His-D-PheArg-T rp-Gaba-Cys)-NH2</td><td> 0,560</td><td> 39,2</td><td> 2,94</td><td> 2,73</td><td> 0,19</td><td>SEKW. NR ID:33</td>

<td>Phe-c(Cys-His-D-Phe-ArgT rp-Gaba-Cy s)-NH&gt;</td><td> 0,186</td><td> 15,2</td><td> 4,93</td><td> 0,537</td><td> 0,04</td><td>SEKW. NR ID:34</td>

<td>Ac-N le-c(Cys-3-Pal-D-PheArg-Trp»-Gaba-Cys)-NH2</td><td> 21,1</td><td> 151</td><td> 10,4</td><td> 92,6</td><td> 2,03</td><td>SEKW. NR ID:35</td>

<td>Ac-Nle-c(Cys-D-Ala-His-DPhe-Arg-T rp-Cys)-OH</td><td> 30,7</td><td> 152</td><td> 15,6</td><td> 114</td><td> 1,97</td><td>SEKW. NR ID:36</td>

<td>Ac-Nle-c(Cy s-His-Phe-ArgD-T rp-Gaba-Cys)-NbŁ&gt;</td><td> 5,20</td><td> 150</td><td> 138</td><td> 20,3</td><td> 0,04</td><td>SEKW. NR ID:37</td>

<td>Ac-Nle-c( Asp-D-Ala-His-DPhe-Arg-Bal-Ala-Lys)-NH2</td><td> 4,89</td><td> 290</td><td> 21,3</td><td> 11,1</td><td> 0,23</td><td>SEKW. NR ID:58</td>

<td>Ac-N le-c(Cys-D-Ala-His-D2-Na 1 -Arg-Trp-Cysj-Nbh</td><td> 25,5</td><td> 3,82</td><td> 7,61</td><td> 102</td><td> 3,35</td><td>SEKW. NR ID:16</td>

<td>Ac-N le-c(Cy s-D-Ala-H is-D2-Nal-Arg-2-Na]-Cys)-Ntt&gt;</td><td> 32,5</td><td> 5,85</td><td> 2,53</td><td> 94,6</td><td> 12,85</td><td>SEKW. NR ID:16</td>

<td>Ac-Nle-c(Cys-D-Ala-His-D2-Nal-Arg-Bal-Cys)-NH2</td><td> 22,2</td><td> 12,7</td><td> 16,6</td><td> 125</td><td> 1,34</td><td>SEKW. NR ID:20</td>

<td>Ac-Nle-c(Asp-His-D-2-NalArg-Trp-Al a -Ly s)-NH&gt;</td><td> 1,17</td><td> 1,56</td><td> 0,277</td><td> 3,24</td><td> 4,22</td><td>SEKW. NR ID:38</td>

<td>Ac-Nle-c(Asp-His-D-2-NalArg-Trp^-Ala-Lys)-NH&gt;</td><td> 0,648</td><td> 2,78</td><td> 0,329</td><td> 1,4</td><td> 1,97</td><td>SEKW. NR ID:38</td>

<td>Ac-Nle-c(Cys-His-D-2-NalArg-T rp-Gaba-Cy s)-NH2</td><td> 0,393</td><td> 1,86</td><td> 0,375</td><td> 1,11</td><td> 1,05</td><td>SEKW. NR ID:39</td>

EP 2 236 151 B1

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-Nle-c(Cys-His-D-2-NalArg-T rp-Ahx-Cys)-NTh</td><td> 0,333</td><td> 2,91</td><td> 0,998</td><td> 0,366</td><td> 0,33</td><td>SEKW. NR ID:39</td>

<td>Ac-h Phe-c( Asp-Hi s-D-2Nal-Arg-Trp-Gaba-Lys)NHz</td><td> 0,461</td><td> 2,45</td><td> 0,931</td><td> 1,37</td><td> 0,50</td><td>SEKW. NR ID:40</td>

<td>Ac-Cha-c(Asp-His-D-2-NaJArg-T rp-Gaba-Lys)-NTL·</td><td> 0,576</td><td> 3,98</td><td> 2,82</td><td> 3,91</td><td> 0,20</td><td>SEKW. NR ID:40</td>

Tablica 2C

<td>Relationship</td><td>Ki hMC 1-R</td><td>Ki hMC 3-R</td><td>Ki hMC 4-R</td><td>Ki hMC 5-R</td><td>Ki hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-Arg-c(Cys-D-Ala-His-D2-Nal-Arg-Trp-Cys)-NH2</td><td> 17,9</td><td> 1,68</td><td> 0,256</td><td> 23,4</td><td> 69,9</td><td>SEKW. NR ID:49</td>

Cyclic AMP bioassay [0095] Intracellular cyclic AMP (cAMP) levels were determined by electrochemoluminiscence (ECL) (Meso Scale Discovery®, Gaithersburg, MD; hereinafter referred to as MSD). CHOK1 cells stably expressing hMC receptor subtypes were suspended in RMPI 1640® assay buffer (RMPI 1640 buffer contains 0.5 mM isobutyl methylxanthine (IBMX) and 0.2% protein cocktail (MSD blocker A)). Transgenic CHO-K1 cells stably expressing 1, 3, 4 or 5 subtypes of the hMC receptor were aliquotted at a density of about 7000 cells / well into 384-well Multi-Array® (MSD) plates containing integrated carbon electrodes and coated with anti-cAMP antibody. Increasing concentrations of test compounds were added and the cells were incubated for about 40 minutes at a temperature of about 37 ° C. After this incubation, lysis buffer (HEPES buffered saline, added) was added MgCl₂ and Triton X-100® (pH 7.3) containing 0.2% protein cocktail and 2.5 nM TAG ™ labeled with cAMP ruthenium (MSD) and the cells were incubated for about 90 minutes at room temperature. At the end of the second incubation, read buffer (Tris buffered solution containing ECL and Triton 100-100 pH 7.8 pH corrector) was added and cAMP levels in cell lysates were immediately determined by ECL detection using a Sector Imager 6000 reader® (MSD). Data were analyzed using computer aided non-linear regression analysis (XL fit; IDBS) and reported as EC value₅₀ or as the Kb value.

[0096] EC₅₀ means the concentration of agonist compound necessary to obtain a 50% maximal response, e.g., 50% of the maximum cAMP level as determined in the assay described above. The Kb value reflects the potency of the antagonist and is determined by Schild's method of analysis. Briefly, concentration-response curves are plotted in the presence of increasing antagonist concentrations. Layer Kb is the antagonist concentration at which a 2-fold shift in the concentration-response curve for the agonist is obtained. It is calculated by extrapolating the line on the Schild chart to zero on the y axis.

[0097] In the test described above, selected compounds were tested and the results are shown in Tables 3A, 3B, 3C and 3D.

EP 2 236 151 B1

TABLES 3A, 3B, 3C and 3D - Data from cAMP bioassay for selected compounds [0098]

Table 3A

<td>Relationship</td><td>^EC50 hMC1-R</td><td>^EC50 hMC3-R</td><td>^EC50 hMC4-R</td><td>^EC50 hMC5-R</td><td>EC₅₀ hMC1-R / MC4-R</td><td>SEQ. NO ID:</td>

<td>Ac-Arg-c (Cys-His-DAla-D-PheArg-Trp-Cys) -NH2</td><td> 5,79</td><td> 5,25</td><td> 0,313</td><td> 1630</td><td> 18,0</td><td>SEQ. ID NO: 50</td>

<td>Ac-D-Arg-c (Cys-DAla-His-D-PheArg-T rp-Cys) -N Ha</td><td> 6,17</td><td> 5,6</td><td> 0,397</td><td> 1020</td><td> 16,0</td><td>SEQ. ID NO: 50</td>

<td>Ac-D-Arg-c (Cys-DAla-His-D-PheArg-T rp-Pen) -N H&gt;</td><td> 26,5</td><td> 10,5</td><td> 0,493</td><td> 2440</td><td> 54,0</td><td>SEKW. NR ID:51</td>

<td>Ac-D-Arg-c(CysHis-D-Phe-ArgTrp-Gaba-Pen)-N H2</td><td> 8,43</td><td> 32,4</td><td> 0,959</td><td> 2140</td><td> 9,0</td><td>SEKW. NR ID:52</td>

<td>Ac-Arg-c(Cys-HisD-Phe-Arg-T rpGaba-Pen)-NH2</td><td> 4,23</td><td> 8,09</td><td> 0,719</td><td> 23,2</td><td> 6,0</td><td>SEKW. NR ID:52</td>

<td>Ac-Arg-c(Cys-DAla-His-D-PheArg-Trp-Pen)-NH&gt;</td><td> 48,3</td><td> 13,3</td><td> 0,79</td><td> 10000</td><td> 61,0</td><td>SEKW. NR ID:51</td>

<td>Ac-D-Arg-c (AspHis-D-Phe-ArgTrp-Al a-Ly s)-N H2</td><td> 1,48</td><td> 5,76</td><td> 0,078</td><td> 297</td><td> 19,0</td><td>SEKW. NR ID:53</td>

<td>Ac-Arg-c( Asp-HisD-Phe-Arg-TrpAla-Lys)-NH&gt;</td><td> 1,39</td><td> 2,89</td><td> 0,055</td><td> 467</td><td> 25,0</td><td>SEKW. NR ID:53</td>

<td colspan="7">ND = nie oznaczono</td>

Tablica 3B

<td>Relationship</td><td>EC50 hMC 1-R</td><td>EC50 hMC 3-R</td><td>^EC50 hMC4-R</td><td>^EC50 hMC5-R</td><td>EC50 hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

EP 2 236 151 B1

<td>Relationship</td><td>EC50 hMC 1-R</td><td>EC50 hMC 3-R</td><td>^EC50 hMC4-R</td><td>^EC50 hMC5-R</td><td>EC₅₀ hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-Nle-c(Cys-D-Ala-HisD-Phe-Arg-T rp-Cys)NPE</td><td> 2,4</td><td> 0,33</td><td> 0,078</td><td> 420</td><td> 31</td><td>SEKW. NR ID:7</td>

<td>D-Phe-c(Cys-His-D(Et)Tyr-Arg-Trp-P-AlaD-Cys)-Thr-NH2</td><td> 0,35</td><td> 1,1</td><td> 0,11</td><td> 0,37</td><td> 3</td><td>SEKW. NR ID:24</td>

<td>Nle-c(Cys-His-D-PheArg-T rp-Apn-Cys)-NH2</td><td> 0,31</td><td> 0,27</td><td> 0,018</td><td> 3,1</td><td> 17</td><td>SEKW. NR ID:27</td>

<td>Ac-Nle-c(Cys-His-D-PheArg-Trp-Gaba-Pen)-NEk</td><td> 0,28</td><td> 0,24</td><td> 0,028</td><td> 3,9</td><td> 10</td><td>SEKW. NR ID:32</td>

<td>Nle-c(Cys-His-D-PheArg-T rp-Gaba-Cys)-NEh</td><td> 0,37</td><td> 0,1</td><td> 0,021</td><td> 1,7</td><td> 18</td><td>SEKW. NR ID:34</td>

<td>Ac-Nle-c(Asp-EIis-DPhe-Arg-Tr ρ-β-Al a-Ly s)NEk</td><td> 0,834</td><td> 0,145</td><td> 0,128</td><td> 2,79</td><td> 6,52</td><td>SEKW. NR ID:1</td>

<td>Ac-Nle-c(Cys-His-D-PheArg-Tr p- A pn-Cy s)-NEh</td><td> 0,76</td><td> 0,199</td><td> 0,0492</td><td> 1,73</td><td> 15,45</td><td>SEKW. NR ID:2</td>

<td>Ac-Cha-c(Asp-His-DPhe-Arg-Trp-Gaba-Lys)NEk</td><td> 3,26</td><td> 0,189</td><td> 0,0949</td><td> 30,2</td><td> 34,35</td><td>SEKW. NR ID:6</td>

<td>Ac-Nle-c(Asp-His-DPhe-Arg-Trp-Gaba-Lys)NH&gt;</td><td> 1,37</td><td> 0,628</td><td> 0,131</td><td> 3,48</td><td> 10,46</td><td>SEKW. NR ID:6</td>

<td>Ac-hCha-c(Asp-His-DPhe-Arg-Trp-Gaba-Lys)NEk</td><td> 2,27</td><td> 3,32</td><td> 7,24</td><td> 415</td><td> 0,31</td><td>SEKW. NR ID:11</td>

<td>Ac-Nle-c(Pen-D-Ala-HisD-Phe-Arg-T rp-Cys)NH2</td><td>ND</td><td> 1,89</td><td> 0,531</td><td>ND</td><td>ND</td><td>SEKW. NR ID:21</td>

<td>Ac-Nle-c(Cys-D-Ala-EIisD-Phe-Arg-T rp-Pen)NEk</td><td> 14,3</td><td> 2,03</td><td> 0,183</td><td> 2240</td><td> 78,14</td><td>SEKW. NR ID:22</td>

<td>D-Phe-c(Cys-His-D(Et)Tyr-h Arg-Trp-β-AlaD-Cys)-Thr-NEE</td><td> 0,345</td><td> 2,71</td><td> 5376</td><td> 2,38</td><td> 0,06</td><td>SEKW. NR ID:24</td>

<td>D-Phe-c(Cys-Elis-D(Et)Tyr-hArg-Bip-P-AlaD-Cys)-Thr-NEk</td><td> 0,685</td><td> 81,8</td><td> 86,9</td><td> 31,8</td><td> 0,01</td><td>SEKW. NR ID:26</td>

<td>Ac-Nle-c(Asp-D-Ala-HisD-Phe-Arg-Bal-Lys)-NEk</td><td> 0,931</td><td> 3,22</td><td> 1,65</td><td> &gt;10000</td><td> 0,56</td><td>SEKW. NR ID:28</td>

EP 2 236 151 B1

<td>Relationship</td><td>EC50 hMC 1-R</td><td>EC50 hMC 3-R</td><td>^EC50 hMC4-R</td><td>^EC50 hMC5-R</td><td>EC₅₀ hMC1-R /MC4-R</td><td>SEKW. NR ID:</td>

<td>Ac-Nle-c(Cys-D-Leu-HisD-Phe-Arg-T rp-Cy s)NH&gt;</td><td> 3,24</td><td> 0,465</td><td> 0,0915</td><td> 78,5</td><td> 35,41</td><td>SEKW. NR ID:30</td>

<td>Ac-N le-c(Cys-D-ChaHis-D-Phe-Arg-T rp-Cys)NH2</td><td> 0,819</td><td> 0,541</td><td> 0,453</td><td> 45,3</td><td> 1,81</td><td>SEKW. NR ID:30</td>

<td colspan="7">ND = nie oznaczono</td>

Tablica 3C

<td>Relationship</td><td>EC50 hMC1-R</td><td>Kb hMC3-R</td><td>Kb MC4-R</td><td>EC50 hMC5-R</td><td>SEKW. NR ID:</td>

<td rowspan="2">Ac-Nle-c(Cys-D-Ala-HisD-2-Nal -Arg-Trp-Cys)NH2</td><td rowspan="2"> 17,6</td><td rowspan="2"> 12,4</td><td rowspan="2"> 38,8</td><td rowspan="2"> 11,8</td><td>SEKW. NR ID:16</td>

<td></td>

<td>Ac-Nle-c( Asp-H is-D-2Nal-Arg-Trp-Ala-Lys)NH2</td><td> 0,619</td><td> 2,98</td><td> 0,109</td><td> 0,189</td><td>SEKW. NR ID:38</td>

<td rowspan="2">Ac-Nle-c(Asp-His-D-2Nal-Arg-Trp-P-Ala-Lys)NH2</td><td rowspan="2"> 0,913</td><td rowspan="2"> 0,536</td><td rowspan="2"> 0,346</td><td rowspan="2"> 0,489</td><td>SEKW. NR ID:38</td>

<td></td>

<td rowspan="2">Ac-Nle-c(Cys-His-D-2Nal-Arg-Trp-Gaba-Cys)NH2</td><td rowspan="2"> 0,231</td><td rowspan="2"> 18,4</td><td rowspan="2"> 0,782</td><td rowspan="2"> 0,153</td><td>SEKW. NR ID:39</td>

<td></td>

<td rowspan="2">Ac-Nle-c(Cys-His-D-2Nal-Arg-Trp-Ahx-Cys)NH2</td><td rowspan="2"> 0,581</td><td rowspan="2"> 10,8</td><td rowspan="2"> 0,967</td><td rowspan="2"> 0,126</td><td>SEKW. NR ID:39</td>

<td></td>

<td>Ac-hPhe-c(Asp-His-D-2Nal-Arg-T rp-Gaba-Ly s)NH2</td><td> 0,413</td><td> 9,32</td><td> 0,824</td><td> 0,307</td><td>SEKW. NR ID:40</td>

<td rowspan="2">Ac-Cha-c( Asp-H is-D-2N a 1-Arg-T rp-Gaba-Lys)NH2</td><td rowspan="2"> 1,27</td><td rowspan="2"> 3,02</td><td rowspan="2"> 0,442</td><td rowspan="2"> 0,736</td><td>SEKW. NR ID:40</td>

<td></td>

<td rowspan="2">Ac-Nle-c(Cys-D-AlaHis-D-2-Nal-Arg-l-NalCys)-NH₂</td><td rowspan="2"> 383</td><td rowspan="2"> 61,5</td><td rowspan="2"> 53,6</td><td rowspan="2"> 2842</td><td>SEKW. NR ID:16</td>

<td></td>

Tablica 3D

<td>Relationship</td><td>EC50 hMC1-R</td><td>Kb hMC3-R</td><td>Kb MC4-R</td><td>EC50 hMC5-R</td><td>SEKW. NR ID:</td>

<td>Ac-Arg-c(Cys-D-Ala-HisD-2-Nal-Arg-Trp-Cys)NH2</td><td> 193</td><td> 5,72</td><td> 1,58</td><td> 1111</td><td>SEKW. NR ID:49</td>

EP 2 236 151 B1

Example 4: In vivo studies [0099] The compounds described herein can be tested and tested for effects on food intake and / or body weight according to the following procedures. It will be apparent to those skilled in the art that procedures similar to those described herein can be used to study the effects of compounds on food intake and / or body weight. [0100] The following compounds were tested in vivo - ligands that activate melanocortin receptors (Table 4):

Table 4

<td>Ligand designation</td><td>Structure</td>

<td>Relationship A</td><td>Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ SEKW. NR ID:7</td>

<td>Relationship B</td><td>Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂ SEKW. NR ID:22</td>

<td>Relationship C</td><td>Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂ SEKW. NR ID:32</td>

<td>Relationship D</td><td>D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-e-Ala-D-Cys)-Thr-NH₂ SEKW. NR ID:24</td>

<td>Relationship E</td><td>Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ SEKW. NR ID:50</td>

<td>Relationship F</td><td>Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂SEKW. NR ID:50</td>

<td>Relationship G</td><td>Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂ SEKW. NR ID:51</td>

Eksperymenty karmienia w warunkach ostrych (na czczo) [0101] Samce szczurów Sprague Dawley (250 g) hodowano w oddzielnych klatkach i utrzymywano w warunkach light: darkness 12:12 hours. Rats were fasted 18 hours before the start of the experiment and were given access to water ad libitum. At time 0, rats were injected subcutaneously (sc) with selected compounds at doses of 500 or 100 nmol / kg, or vehicle, and then fed with food. About 1.2, 3, 4, 5 and 6 hours after the injection, individual food intake was measured. Data for selected compounds are shown in Figures 1A and 1B.

Feeding experiments under stringent (non-fasting) conditions [0102] Male Sprague Dawley rats (250 g) were housed in separate cages and kept under light: darkness 12:12 hours. During the whole experiment, rats had access to food and water ad libitum. At time 0, rats were injected sc with selected compounds at doses of 500 or 100 nmol / kg, or vehicle. About 1.2, 3, 4, 5 and 6 hours after the injection, individual food intake was measured

Prolonged feeding experiments [0103] Male Sprague Dawley rats (250 g) were housed in separate cages and kept in light: dark 12:12 hours with food and water ad libitum. Rats were injected

EP 2 236 151 B1

Sc 3 x / day (about 08.00 hours, 12.00 hours and 16.00 hours) for 7 days compound in different doses or vehicle. Individual body weights and food intake were measured daily. Data for selected compounds of the invention are shown in Figures 2A and 2B, Figures 3A and 3B and Figures 4A and 4B.

Administration and use [0104] The peptides described herein can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, salts formed with organic acids (eg, acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, phosphonic or pamoate toluene), with inorganic acids (eg, hydrochloric acid, sulfuric acid or phosphoric acid) and with polymeric acids (e.g. cheap acid acid, carboxymethyl cellulose, polylactic acid, polyglycolic acid or poly (lactic acid glycolic acid) copolymers. A typical method for producing peptide salts is well known in the art and includes standard salt exchange methods. Accordingly, the TFA salt of the peptide (the TFA salt is obtained by purifying the peptide by preparative HPLC, eluting with buffer solutions containing TFA) can be converted into another salt, such as acetate, by dissolving the peptide in a small amount of 0.25 N aqueous acetic acid . The resulting solution is applied to a semi-preparative HPLC column (Zorbax, 300 SB, C-8). The column is eluted with: (1) 0.1N aqueous ammonium acetate solution for 0.5 hour; (2) 0.25N aqueous acetic acid for 0.5 hour; and (3) a linear gradient (20% to 100% solution B over 30 minutes) at a flow rate of 4 ml / minute (solution A is 0.25N aqueous acetic acid; solution B is 0.25N acetic acid in acetonitrile / water, 80:20). Fractions contain The peptide is collected and lyophilized to dryness. [0105] As is well known to those skilled in the art, known and potential uses of peptides with agonist activity or melanocortin receptor (MC-R) antagonist activity are diverse and numerous, and therefore administration of the compounds described herein to induce an agonist effect the same effects and uses as for melanocortin alone.

The present invention includes within its scope pharmaceutical compositions comprising, as active ingredient, a selective melanocortin 4 receptor agonist of the formula Ac-Arg-c (Cys-D-Ala-His-D-PheArg-Trp-Cys) -NH₂ (SEQ ID NO: 50) in combination with a pharmaceutically acceptable carrier.

[0107] The dose of active ingredient in the compositions of the present invention may vary; however, an amount of active ingredient is necessary in which a suitable dosage form can be obtained. The choice of dose depends on the desired therapeutic effect, route of administration and duration of treatment.

Generally, for the activity of the present invention, the effective dose is in the range of 1x10^-7 it is 200 mg / kg / day, preferably 1x10^-4 up to 100 mg / kg / day and can be administered as a single dose or as divided into multiple doses.

[0108] The compounds of the present invention may be administered by the oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant) route, intranasal, vaginal, rectal, sublingual or local route of administration and may be formulated with pharmaceutically acceptable carriers to provide formulations suitable for each of these routes of administration.

[0109] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier, such as sucrose, lactose or starch. As is usual practice, such solid dosage forms may also contain additional substances other than inert diluents, e.g., lubricants, such as magnesium stearate. In the case of capsules, the dosage forms may also contain buffering agents. Tablets and pills can further be made with enteric coatings.

[0110] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents typically used in the art, such as water. In addition to such inert diluents, such compositions may also include auxiliary substances such as wetting agents, emulsifying and suspending agents as well as sweetening, flavoring and flavoring agents.

[0111] Formulations of the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or carriers are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and injectable organic esters such as ethyl oleate. Such dosage forms may also contain auxiliary substances such as preserving, wetting, emulsifying and dispersing agents. Such preparations may be sterilized, for example, by filtration through a bacterial-retaining filter, by incorporating sterilizing substances into the composition, by irradiating the composition or by heating. These formulations can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium immediately before use.

[0112] The compositions for rectal or vaginal administration are preferably suppositories, which may contain, in addition to the active substance, excipients such as cocoa butter or suppository wax. [0113] Compositions for nasal or sublingual administration are also prepared using standard excipients known in the art.

[0114] In addition, the compound of the present invention can be administered in a sustained release composition such as described in the following patents and patent applications. U.S. Patent No. 5,672,659 describes sustained release compositions comprising a bioactive agent and polyester. U.S. Patent No. 5,595,760 describes sustained release compositions containing a bioactive agent in the form of a gel. U.S. Patent No. 5,821,221 describes sustained release compositions comprising a bioactive agent and chitosan. U.S. Patent No. 5,916,883 describes sustained release compositions comprising a bioactive agent and cyclodextrin.

SEQUENCE LIST [0115] &lt;110&gt; BIOMEASURE, INCORPORATED &lt;120&gt; MELANOCORTIN RECEPTOR LIGANDS &lt;130&gt; 146P2 / PCT2

EP 2 236 151 B1 &lt;140&gt; PCT / US2006 / 26586 &lt;141&gt; 2006-07-10 &lt;150&gt; US 60/748850 &lt;151&gt; 2005-12-09 &lt;150&gt; US 60/697779 &lt;151&gt; 2005-07- 08 &lt;160&gt; 61 &lt;170&gt; PatentIn version 3.3 &lt;210&gt; 1 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = beta-Ala or 1-amino-1-cyclohexanecarboxylic acid (A6c) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 1

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 2 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence

&lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 6-aminohexanoic acid (Ahx) or 5-aminopentanoic acid (Apn) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 2 xaa cys His Xaa Arg Trp Xaa Cys 1 5 &lt;210&gt; 3 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = Ala, beta-Ala or 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9) .. (9) &lt;223&gt; AMIDIFY &lt;400&gt; 3

Xaa Cys His Xaa Arg Trp Xaa Xaa Thr 1 5 &lt;210&gt; 4 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = kwas 5-aminopentanowy (Apn) &lt;220&gt;

&lt;221&gt; MOD_RES

EP 2 236 151 B1 &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 4

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 5 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = kwas 1-amino-1-cykloheksanokarboksylowy (A6c) modyfikowany acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = kwas 4-aminomasłowy (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 5 xaa Asp His Xaa Arg Trp xaa Lys 1 5 &lt;210&gt; 6 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = D-beta-(2-naftylo)Ala (D-2-Nal), beta-cykloheksylo-Ala (Cha) lub Nle, wszystkie modyfikowane acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = kwas 4-aminomasłowy (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 6

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 7 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala, beta-Ala, kwas 4-aminomasłowy (Gaba), kwas alfa-aminoizomasłowy (Aib) lub Gly &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 7

Xaa Cys Xaa His Xaa Arg Trp Cys 1 5 &lt;210&gt; 8 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (2)..(2) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = Ala, D-Ala, beta-Ala, kwas 4-aminomasłowy (Gaba), kwas alfa-aminoizomasłowy (Aib) lub Gly &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES

EP 2 236 151 B1 &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 8 xaa Xaa xaa His Xaa Arg Trp cys 1 5 &lt;210&gt; 9 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala, beta-Ala, kwas 4-aminomasłowy (Gaba), kwas alfa-aminoizomasłowy (Aib) lub Gly &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 9

Xaa Cys Xaa His Xaa Arg Trp Xaa 1 5

EP 2 236 151 B1 &lt;210&gt; 10 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (2)..(2) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = Ala, D-Ala, beta-Ala, kwas 4-aminomasłowy (Gaba) lub kwas alfa-aminoizomasłowy (Aib) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 10

Xaa Xaa xaa His Xaa Arg Trp Xaa 1 5 &lt;210&gt; 11 &lt;211&gt; 8

EP 2 236 151 B1 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = kwas oktahydroindolo-2-karboksylowy (Oic), cykloheksylo-Gly (Chg), homo-cykloheksylo-Ala (hCha), D-betacykloheksylo-Ala (D-Cha), kwas nipekotynowy (Nip), homo-Pro (hPro), homo-Leu (hLeu), Phe, D-Phe, D-cykloheksylo-Gly (D-Chg) homo-Phe (hPhe), beta-homoMet (beta-hMet) lub kwas 4-aminomasłowy (Gaba), wszystkie modyfikowane acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = kwas 4-aminomasłowy (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 11

Xaa Asp His xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 12 &lt;211&gt;8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = beta-cykloheksylo-Ala (Cha) modyfikowana n-butanoilem

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = kwas 4-aminomasłowy (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 12 xaa Asp His Xaa Arg Trp xaa Lys 1 5 &lt;210&gt; 13 &lt;211&gt;8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = beta-cykloheksylo-Ala (Cha), homo-cykloheksylo-Ala (hCha), Leu, homo-Leu (hLeu) lub Phe, wszystkie modyfikowane acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (6)..(6) &lt;223&gt; Xaa = D-T rp &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 13 xaa Asp His xaa Arg xaa Ala Lys 1 5 &lt;210&gt; 14 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6)..(6) &lt;223&gt; Xaa = D-Trp &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = D-Ala, beta-Ala, kwas 4-aminomasłowy (Gaba), kwas 7-aminoheptanowy (Aha) lub kwas 5aminopentanowy (Apn) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE

EP 2 236 151 B1 &lt;400&gt; 14

Xaa Asp His Xaa Arg Xaa Xaa Lys 1 5 &lt;210&gt; 15 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6)..(6) &lt;223&gt; Xaa = D-Trp &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = kwas 5-aminopentanowy (Apn), kwas 4-aminomasłowy (Gaba), kwas 6-aminoheksanowy (Ahx), beta-Ala, D-Ala &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 15 xaa Cys His Xaa Arg Xaa Xaa Cys 1 5 &lt;210&gt; 16 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna

EP 2 236 151 B1 &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-beta-(2-naftylo)Ala (D-2-Nal) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = Trp, beta-(2-naftylo)Ala (2-Nal) lub beta-(1-naftylo)Ala (1-Nal) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 16 xaa cys xaa His xaa Arg Xaa cys 1 5 &lt;210&gt; 17 &lt;211&gt;8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana n-butanoilem &lt;220&gt;

&lt;221&gt; DOMENA

EP 2 236 151 B1 &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = beta-(2-naftylo)Ala (2-Nal) lub Trp &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 17

Xaa Cys Xaa His Xaa Arg Xaa Cys 1 5 &lt;210&gt; 18 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = beta-(2-naftylo)Ala (2-Nal), beta-(1-naftylo)Ala (1-Nal) lub 3-benzotienylo-Ala (Bal) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 18 xaa Cys xaa His xaa Arg xaa cys 1 5 &lt;210&gt; 19 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 19

EP 2 236 151 B1

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5

PRT

Sekwencja sztuczna

Ligand receptora melanokortyny

MISC-FEATURE (1)..(1)

Xaa = Nle modyfikowana acylem (AC)

DOMENA (2)..(8)

Cykliczna

MISC_FEATURE (3)..(3)

Xaa = D-Ala

MISC_FEATURE (5)..(5)

Xaa = D-beta-2-naftylo-Ala (D-2-Nal)

MISC_FEATURE (7) ..(7)

Xaa = 3-benzotienylo-Ala (Bal)

MOD_RES (8) ..(8)

AMIDOWANIE

Xaa Cys Xaa Hi s Xaa Arg Xaa Cys 1 5

PRT

Sekwencja sztuczna

Ligand receptora melanokortyny

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (2)..(2) &lt;223&gt; Xaa = penicyloamina (Pen) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 21

Xaa Xaa Xaa His Xaa Arg Trp Cys 1 5 &lt;210&gt; 22 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (2)..(2) &lt;223&gt; Xaa = Cys lub penicyloamina (Pen) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = penicyloamina (Pen) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 22

Xaa Xaa xaa His Xaa Arg Trp Xaa 1 5 &lt;210&gt; 23 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = homo-Arg (hArg) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = beta-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9)..(9) &lt;223&gt; AMIDOWANIE &lt;400&gt; 23

Xaa Cys His Xaa Xaa Trp xaa xaa Thr 1 5 &lt;210&gt; 24 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-(Et)Tyr &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = Arg lub homo-Arg (hArg)

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = beta-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9)..(9) &lt;223&gt; AMIDOWANIE &lt;400&gt; 24 xaa cys His xaa xaa Trp Xaa Xaa Thr 1 5 &lt;210&gt; 25 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6)..(6) &lt;223&gt; Xaa = 4,4'-bifenylo-Ala (Bip) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = beta-Ala

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9)..(9) &lt;223&gt; AMIDOWANIE &lt;400&gt; 25

Xaa Cys His Xaa Arg Xaa Xaa Xaa Thr 1 5 &lt;210&gt; 26 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe lub D-(Et)Tyr &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = homo-Arg (hArg) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6)..(6) &lt;223&gt; Xaa = 4,4'-bifenylo-Ala (Bip) &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = beta-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9)..(9) &lt;223&gt; AMIDOWANIE &lt;400&gt; 26

Xaa Cys His xaa xaa Xaa Xaa Xaa Thr 1 5 &lt;210&gt; 27 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4)..(4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7)..(7) &lt;223&gt; Xaa = kwas 5-aminopentanowy (Apn) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 27

EP 2 236 151 B1

Xaa Cys His Xaa Arg Trp xaa cys 1 5

PRT

Sekwencja sztuczna

Ligand receptora melanokortyny

MISC_FEATURE (1)..(1)

Xaa = Nle modyfikowana acylem (AC)

DOMENA (2)..(8)

Cykliczna

MISC_FEATURE (3)..(3)

Xaa = D-Ala

MISC_FEATURE (5)..(5)

Xaa = D-Phe

MISC_FEATURE (7) ..(7)

Xaa = Trp lub 3-benzotienylo-Ala (Bal)

MOD_RES (8) ..(8)

AMIDOWANIE

Xaa Asp Xaa His Xaa Arg Xaa Lys 1 5

PRT

Sekwencja sztuczna

Ligand receptora melanokortyny

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8)..(8) &lt;223&gt; Xaa = penicyloamina (Pen) lub Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; C-koniec stanowi wolny kwas &lt;400&gt; 29

Xaa Cys Xaa His Xaa Arg Trp Xaa 1 5 &lt;210&gt; 30 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Sekwencja sztuczna &lt;220&gt;

&lt;223&gt; Ligand receptora melanokortyny &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1)..(1) &lt;223&gt; Xaa = Nle modyfikowana acylem (AC) &lt;220&gt;

&lt;221&gt; DOMENA &lt;222&gt; (2)..(8) &lt;223&gt; Cykliczna

EP 2 236 151 B1 &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3)..(3) &lt;223&gt; Xaa = kwas D-alfa-aminomasłowy (D-Abu), D-Val, D-Ile, D-Leu, D-tert-Leu (D-Tle) lub D-betacykloheksylo-Ala (D-cha) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5)..(5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8)..(8) &lt;223&gt; AMIDOWANIE &lt;400&gt; 30 xaa cys xaa His Xaa Arg Trp Cys 1 5 &lt;210&gt; 31 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (2) .. (2) &lt;223&gt; Xaa = penicillamine (Pen) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 31

Xaa Xaa His Xaa Arg Trp Xaa Cys 1 5 &lt;210&gt; 32 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (2) .. (2) &lt;223&gt; Xaa = Cys or penicillamine (Pen) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = penicillamine (Pen) &lt;220&gt;

&lt;221&gt; MOD_RES

EP 2 236 151 B1 &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 32

Xaa Xaa His Xaa Arg Trp Xaa Xaa 1 5 &lt;210&gt; 33 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Leu, beta-cyclohexyl-Ala (Cha), Ile, Phe, Val or beta (2-naphthyl) Ala (2-Nal) , all acyl (AC) &lt;220&gt; modified

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 33 xaa Cys His Xaa Arg Trp xaa cys 1 5 &lt;210&gt; 34 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; melanocortin receptor ligand

&lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Nle or Phe &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 34

Xaa Cys His Xaa Arg Trp Xaa Cys 1 5 &lt;210&gt; 35 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = beta- (3-pyridyl) Ala (3-Pal) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 35

Xaa Cys Xaa Xaa Arg Trp Xaa Cys 1 5 &lt;210&gt; 36 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES

EP 2 236 151 B1 &lt;222&gt; (8) .. (8) &lt;223&gt; The C-terminus is free acid &lt;400&gt; 36 xaa Cys Xaa His Xaa Arg Trp Cys 1 5 &lt;210&gt; 37 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6) .. (6) &lt;223&gt; Xaa = DT rp &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 37

Xaa Cys His Phe Arg Xaa Xaa Cys 1 5 &lt;210&gt; 38 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; melanocortin receptor ligand

&lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-beta- (2-naphthyl) Ala (D-2-Nal) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = Ala or beta-Ala &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 38

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 39 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-beta- (2-naphthyl) Ala (D-2-Nal)

&lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) or 6-aminohexanoic acid (Ahx) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 39 xaa cys His xaa Arg Trp xaa cys 1 5 &lt;210&gt; 40 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = homo-Phe (hPhe) or beta-cyclohexyl-Ala (cha), both acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-beta- (2-naphthyl) Ala (D-2-Nal) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATING &lt;400&gt; 40 xaa Asp His Xaa Arg Trp xaa Lys 1 5

EP 2 236 151 B1 &lt;210&gt; 41 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = beta-Ala or 5-aminopentanoic acid (Apn) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; C-terminus is free acid &lt;400&gt; 41

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 42 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN

EP 2 236 151 B1 &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 6-aminohexanoic acid (Ahx) or 5-aminopentanoic acid (Apn) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; C-terminus is free acid &lt;400&gt; 42 xaa cys His xaa Arg Trp Xaa cys 1 5 &lt;210&gt; 43 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (9) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = Ala, beta-Ala or 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = D-Cys &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9) .. (9) is free acid &lt;223&gt; C-terminus is free acid &lt;400&gt; 43 xaa Cys His xaa Arg Trp Xaa Xaa Thr 1 5 &lt;210&gt; 44 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = beta-cyclohexyl-Ala (Cha), Nle, cyclohexyl-Gly (Chg), D-beta-cyclohexyl-Ala (D-cha) , homo-cyclohexyl-Ala (hcha), D-cyclohexyl-Gly (D-chg) or homo-Phe (hPhe), all modified with acyl (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; C-terminus is free acid &lt;400&gt; 44

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5

EP 2 236 151 B1 &lt;210&gt; 45 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6) .. (6) &lt;223&gt; Xaa = D-Trp &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba), 6-aminohexanoic acid (Ahx), beta-Ala or D-Ala &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; C-terminus is free acid &lt;400&gt; 45 xaa cys His xaa Arg xaa Xaa cys 1 5 &lt;210&gt; 46 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-beta- (2-naphthyl) Ala (D-2-Nal) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = Trp, beta- (2-naphthyl) Ala (2-Nal), beta- (1-naphthyl) Ala (1-Nal) or 3-benzothienylalanine (Bal) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; C-terminus is free acid &lt;400&gt; 46

Xaa Cys Xaa His Xaa Arg Xaa Cys 1 5 &lt;210&gt; 47 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (2) .. (2) &lt;223&gt; Xaa = penicillamine (Pen) &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; C-terminus is free acid &lt;400&gt; 47

Xaa Xaa Xaa His xaa Arg Trp cys 1 5 &lt;210&gt; 48 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = penicillamine (Pen) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; C-terminus is free acid &lt;400&gt; 48

Xaa Cys His Xaa Arg Trp Xaa Xaa 1 5 &lt;210&gt; 49 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (1) .. (1) &lt;223&gt; acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-beta- (2-naphthyl) Ala (D-2-Nal) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 49

Arg Cys xaa His xaa Arg Trp cys 1 5 &lt;210&gt; 50 &lt;211&gt; 8

&lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Arg or D-Arg, both acyl (AC) modified &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 50 xaa Cys Xaa His Xaa Arg Trp Cys 1 5 &lt;210&gt; 51 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = D-Arg or Arg, both modified with acyl (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic

&lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = penicillamine (Pen) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 51 xaa Cys xaa His Xaa Arg Trp xaa 1 5 &lt;210&gt; 52 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = D-Arg or Arg, both acyl (AC) modified &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba)

&lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = penicillamine (Pen) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 52 xaa cys His Xaa Arg Trp Xaa Xaa 1 5 &lt;210&gt; 53 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = D-Arg or Arg, both acyl (AC) modified &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 53

Xaa Asp His Xaa Arg Trp Ala Lys 1 5 &lt;210&gt; 54 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Artificial sequence

&lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (9) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = Gly, D-Ala, beta-Ala, 4-aminobutyric acid (Gaba) or 5-aminopentanoic acid (Apn) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9) .. (9) &lt;223&gt; AMIDIFY &lt;400&gt; 54

<img file="PL2236151T3_D0008.tif" />

5 &lt;210&gt; 55 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MOD_RES

EP 2 236 151 B1 &lt;222&gt; (1) .. (1) &lt;223&gt; acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6) .. (6) &lt;223&gt; Xaa = Trp or beta- (2-naphthyl) alanine (2-Nal) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 55

Cys Glu His xaa Arg xaa Ala cys 1 5 &lt;210&gt; 56 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (1) .. (1) &lt;223&gt; acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (2) .. (2) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE

EP 2 236 151 B1 &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (6) .. (6) &lt;223&gt; Xaa = Trp or beta- (2-naphthyl) Ala (2-Nal) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 56

Cys Xaa His Xaa Arg Xaa Ala Cys 1 5 &lt;210&gt; 57 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (9) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (8) .. (8) &lt;223&gt; Xaa = Ala, beta-Ala or 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES

EP 2 236 151 B1 &lt;222&gt; (9) .. (9) &lt;223&gt; AMIDATION &lt;400&gt; 57

Xaa Cys xaa His Xaa Arg Trp Xaa Cys 1 5 &lt;210&gt; 58 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (9) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Ala &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 3-benzothienyl-Ala (Bal) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (9) .. (9) &lt;223&gt; AMIDIFY &lt;400&gt; 58

Xaa Asp Xaa His Xaa Arg Xaa Ala Lys 1 5 &lt;210&gt; 59 &lt;211&gt; 8

&lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = D-homo-cyclohexyl-Ala (D-hcha) acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 59 xaa Asp His xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 60 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = beta-cyclohexyl-Ala (Cha) modified with n-butyryl &lt;220&gt;

&lt;221&gt; DOMAIN

EP 2 236 151 B1 &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (4) .. (4) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (7) .. (7) &lt;223&gt; Xaa = 4-aminobutyric acid (Gaba) &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDIFY &lt;400&gt; 60

Xaa Asp His Xaa Arg Trp Xaa Lys 1 5 &lt;210&gt; 61 &lt;211&gt; 8 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Melanocortin receptor ligand &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (1) .. (1) &lt;223&gt; Xaa = Not acyl modified (AC) &lt;220&gt;

&lt;221&gt; DOMAIN &lt;222&gt; (2) .. (8) &lt;223&gt; Cyclic &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (3) .. (3) &lt;223&gt; Xaa = D-Glu &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;222&gt; (5) .. (5) &lt;223&gt; Xaa = D-Phe &lt;220&gt;

&lt;221&gt; MOD_RES

EP 2 236 151 B1 &lt;222&gt; (8) .. (8) &lt;223&gt; AMIDATION &lt;400&gt; 61

Xaa cys xaa His xaa Arg Trp Cys 1 5