IL201732A

Melanocortin receptor ligands

Abstract

This record has no abstract on file.

Term

No projected expiry on record.

28 claims: 3 independent, 25 dependent

1
What is claimed is:1. A melanocortin receptor ligand compound according to formula (I): (R2R3)-A1-c (A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1 wherein: A1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val or deleted;A2 is Cys, Pen or Asp;A3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, or D-Val;A4 is His;A5 is D-Phe, D Nal or D-(Et)Tyr;A6 is Arg;A7 is Trp, 2-Nal, Bal, Bip or D-Trp;A8 is Gly, Ala, β-Ala, Gaba, Apn, Ahx or deleted;A9 is Cys, D-Cys, Pen or Lys;A10 is Thr or deleted;and R1 is -OH or -NH2 R2 and R3 is, independently for each occurrence, H or acyl;(I) . when A2 is Cys or Pen, then A9 is Cys, D-Cys or Pen;(II) . when A2 is Asp, then A9 is Lys;(III) . when A1 is deleted, then R2 and R3 cannot both be H;and (IV) . said compound is not Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:50), or a pharmaceutically acceptable salt thereof. 47
27
The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat a disease or condition selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders, Prader-Willi Syndrome, a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, skin cancer, endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, decreased sexual response in females, organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, enhanced immune tolerance, allergies, psoriasis, skin pigmentation depletion, acne, keloid formation, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.
28
The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to modulate ovarian weight, placental development, prolactin secretion, FSH secretion, 78 intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain 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.

Independent claims3

271 paragraphs in 14 sections, as filed

MELANOCORTIN RECEPTOR LIGANDS

BACKGROUND OF THE INVENTION

The present invention is directed to peptides which are ligands of one or more of the melanocortin receptors (MC-R), the pharmaceutically-acceptable salts thereof, to methods of using such peptides to treat mammals and to useful pharmaceutical compositions comprising said peptides.

Melanocortins are a family of regulatory peptides which are formed by posttranslational processing of pro-hormone pro-opiomelanocortin (POMC; 131 amino acids in length). POMC is processed into three classes of hormones; the melanocortins, adrenocorticotropin hormone, and various endorphins (e.g. lipotropin) (Cone, et al., Recent Prog. Horm. Res., 51:287-317, (1996); Cone et al., Ann. N.Y. Acad. Sci., 31:342-363, (1993)).

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

Melanocortin peptides have been shown to exhibit a wide variety of physiological activities including the control of behavior and memory, affecting neurotrophic and antipyretic properties, as well as affecting the modulation of the immune system. Aside from their well known effects on adrenal cortical functions (adrenocorticotropic hormone, ACTH) and on melanocytes (melanocyte stimulating hormone, MSH), melanocortins have also been shown to control the cardiovascular system, analgesia, thermoregulation and the release of other neurohumoral agents including prolactin, luteinizing hormone and biogenic amines (De Wied, D. et al., Methods Achiev. Exp. Pathol. 15:167-199 (1991); De Wied, D. et al., Physiol. Rev. 62:9771059 (1982); Guber, K.A. et al., Am. J. Physiol. 257:R681-R694 (1989); Walker J.M. et al., Science 210:1247-1249 (1980); Murphy, M. T. et al., Science 221:192-193 (1983); Ellerkmann, E. et al., Endocrinol. 130:133-138 (1992) and Versteeg, D. H. G. et al., Life Sci. 38:835-840 (1986)).

It has also been shown that binding sites for melanocortins are distributed in many different tissue types including lachrymal and submandibular glands, pancreas, adipose, bladder, duodenum, spleen, brain and gonadal tissues as well as malignant melanoma tumors. Five melanocortin receptors (MC-R) have been characterized to date. These include melanocyte-specific receptor (MC1-R), corticoadrenal-specific ACTH receptor (MC2-R), melacortin-3 (MC3-R), melanocortin-4 (MC4-R) and melanocortin-5 receptor (MC5-R). All of the melanocortin receptors respond to the peptide hormone class of melanocyte stimulating hormones (MSH) (Cone, R. D. et al., Ann. N.Y. Acad. Sci., 680:342-363 (1993); Cone, R. D. et al., Recent Prog. Horm. Res., 51:287-318 (1996)). MC1-R, known in the art as Melanocyte Stimulating Hormone Receptor (MSH-R), Melanotropin Receptor or Melanocortin-1 Receptor, is a 315 amino acid transmembrane protein belonging to the family of G-Protein coupled receptors. MC1-R is a receptor for both MSH and ACTH. The activity of MC1-R is mediated by G-proteins which activate adenylate cyclase. MC1-R receptors are found in melanocytes and corticoadrenal tissue as well as various other tissues such as adrenal gland, leukocytes, lung, lymph node, ovary, testis, pituitary, placenta, spleen and uterus. MC2-R, also called Adrenocorticotropic hormone receptor (ACTH-R), is a 297 amino acid transmembrane protein found in melanocytes and the corticoadrenal tissue. MC2-R mediates the corticotrophic 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 332 amino acid transmembrane protein which is also expressed in brain as well as placental and gut tissues. MC5-R is a 325 amino acid transmembrane protein expressed in the adrenals, stomach, lung and spleen and very low levels in the brain. MC5-R is also expressed in the three layers of adrenal cortex, predominantly in the aldosterone-producing zona glomerulosa cells.

The five known melanocortin receptors differ, however, in their functions. For example, MC1-R is a G-protein coupled receptor that regulates pigmentation in response to α-MSH, a potent agonist of MC1-R. Agonism of the MC1-R receptor results in stimulation of the melanocytes which causes eumelanin and increases the risk for cancer of the skin. Agonism of MC1-R can also have neurological effects. Stimulation of MC2-R activity can result in carcinoma of adrenal tissue. Recent pharmacological confirmation has established that central MC4-R receptors are the prime mediators of the anorexic and orexigenic effects reported for melanocortin agonists and antagonists, respectively. The effects of agonism of the MC3-R and MC5-R are not yet known. 3

There has been great interest in melanocortin (MC-R) receptors as targets for the design of novel therapeutics to treat disorders of body weight such as obesity and cachexia. Both genetic and pharmacological evidence points toward central MC4-R receptors as the principal target (Giraudo, S. Q. et al., Brain Res., 809:302-306 (1998); Farooqi, I. S. et al., NE J Med., 348:1085-1095 (2003); MacNeil, D. J. et al., Eu. J. Pharm., 44:141-157 (2002); MacNeil, D. J. et al., Eu. J. Pharm., 450:93-109 (2002); Kask, A. et al., NeuroReport, 10:707-711 (1999)). The current progress with receptor-selective agonists and antagonists evidences the therapeutic potential of melanocortin receptor activation, particularly MC4-R.

Agonist, antagonist or other ligand compounds activating one or more melanocortin receptor would be useful for treating a wide variety of indications in a subject in need thereof or at risk thereof including acute and chronic inflammatory diseases such as general inflammation (U.S. Patent No. 6,613,874; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), inflammatory bowel disease (U.S. Patent No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), brain inflammation (Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), sepsis (U.S. Patent No. 6,613,874; U.S. Patent No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)) and septic shock (U.S. Patent No. 6,613,874; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)); diseases with an autoimmune component such as rheumatoid arthritis (U.S. 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, S. J. et al., Curr. Opin. Investig. Drugs, 2:1064-1069 (2001)), and multiple sclerosis ((U.S. Patent No. 6,713,487); metabolic diseases and medical conditions accompanied by weight gain such as obesity (U.S. Patent No. 6,613,874; U.S. Patent No. 6,600,015; Fehm, H. L. et al., J. Clin. Endo. &amp; Metab., 86:1144-1148 (2001); Hansen, M. J. et al., Brain Res., 1039:137-145 (2005); Ye, Z. et al., Peptides, 26:2017-2025 (2005); Farooqi, I. S. et al., NE J Med., 348:1085-1095 (2003); MacNeil, D. J. et al., Eu. J. Pharm., 44:141-157 (2002); MacNeil, D. J. et al., Eu. J. Pharm., 450:93-109 (2002); Kask, A. et al., NeuroReport, 10:707-711 (1999); Schwartz, M. W., J. Clin. Invest., 108:963-964 (2001), Gura, T., Science, 287:1738-1740 (2000), Raffin-Sanson, M. L., Eu. J. Endo., 144:207-208 (2001), Hamilton, B. S. et al., Obesity Res. 10:182-187 (2002)), feeding disorders (U.S. Patent No. 6,720,324; Fehm, H. L. et al., J. Clin. Endo. &amp; Metab., 86:1144-1148 (2001); Pontillo, J. et al., Bioorganic &amp; 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 accompanied by weight loss such as anorexia (U.S. Patent No. 6,613,874; Wisse, B. R. et al., Endo., 142:3292-3301 (2001)), bulimia (U.S. Patent No. 6,720,324), AIDS wasting (Marsilje, T. H. et al., Bioorg. Med. Chem. Lett., 14:3721-3725 (2004); Markison, S. et al., Endocrinology, 146:2766-2773 (2005)), cachexia (U.S. 4

Patent No. 6,613,874; Lechan, R. M. et al., Endo., 142:3288-3291 (2001); Pontillo, J. et al., Bioorganic &amp; Med. Chem. Ltrs., 15:2541-2546 (2005)), cancer cachexia (U.S. Patent No. 6,639,123) and wasting in frail elderly (U.S. Patent No. 6,639,123); diabetes (U.S. Patent No. 6,713,487) and diabetalogical related conditions and complications of diabetes such as retinopathy (U.S. Patent No. 6,525,019); neoplastic proliferation (U.S. Patent No. 6,713,487) such as skin cancer (Sturm, R.A., Melanoma Res., 12:405-416 (2002); Bastiens, M. T. 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); reproductive or sexual medical conditions such as endometriosis (U.S. Patent No. 6,713,487) and uterine bleeding in women (U.S. Patent No. 6,613,874), sexual dysfunction (U.S. Patent No. 6,720,324; Van der Ploeg, L. H. T. et al., PNAS, 99:11381-11386 (2002), Molinoff, P. B. et al., Ann. N.Y. Acad. Sci., 994:96102 (2003), Hopps, C. V. et al., BJU International, 92:534-538 (2003)), erectile dysfunction ((U.S. Patent No. 6,613,874; Diamond, L. E. et al., Urology, 65:755-759 (2005), Wessells, H. et al., Int. J. Impotence Res., 12:S74-S79 (2000), Andersson, K-E. 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, A. M. et al., Society for Neuroscience Abstract, (2003); Wessells, H. et al., J. Urology, 160:389-393 (1998), Rosen, R. C. et al., Int. J. Impotence Res., 16:135-142 (2004), Wessells, H. et al., Peptides, 26:1972-1977 (2005)) and decreased sexual response in females (U.S. Patent No. 6,713,487; Fourcroy, J. L., Drugs, 63:1445-1457 (2003)); diseases or conditions resulting from treatment or insult to the organism such as organ transplant rejection (U.S. 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 to accelerate wound healing (Sharma H. S. et al., Acta. Nerochir. Suppl., 86:399-405 (2003); Sharma H.S., Ann. N.Y. Acad. Sci. 1053: 407-421 (2005); U.S. Patent No. 6,525,019), as well as weight loss caused by chemotherapy, radiation therapy, temporary or permanent immobilization (Harris, R. B. 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 (U.S. Patent No. 6,613,874), hypovolemic shock (U.S. Patent No. 6,613,874), cardiovascular disorders (U.S. Patent No. 6,613,874) and cardiac cachexia (Markison, S. et al., Endocrinology, 146:2766-2773 (2005); pulmonary diseases or conditions such as acute 5 respiratory distress syndrome (U.S. Patent No. 6,350,430; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), chronic obstructive pulmonary disease (U.S. Patent No. 6,713,487), asthma (U.S. Patent No. 6,713,487) and pulmonary fibrosis; to enhance immune tolerance (Luger, T. A. et al., Pathobiology, 67:318-321 (1999)) and to combat assaults to the immune system such as those associated with certain allergies (U.S. Patent No. 6,713,487) or organ transplant rejection (U.S. Patent No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)); treatment of dermatological diseases and conditions such as psoriasis (U.S. Patent No. 6,713,487), skin pigmentation depletion (U.S. Patent No. 6,713,487; Ye, Z. et al., Peptides, 26:2017-2025 (2005)), acne (Hatta, N. et al., J. Invest. Dermatol., 116:564570 (2001); Bohm, M. et al., J. Invest. Dermatol., 118:533-539 (2002)), keloid formation (U.S. Patent No. 6,525,019) and skin cancer (Sturm, R.A., Melanoma Res., 12:405-416 (2002); Bastiens, M. T. et al., Am. J. Hum. Genet., 68:884-894 (2001)); behavioral, central nervous system or neuronal conditions and disorders such as anxiety (U.S. Patent No. 6,720,324; Pontillo, J. et al., Bioorganic &amp; Med. Chem. Ltrs., 15:2541-2546 (2005)), depression (Chaki, S. et al., Peptides, 26:1952-1964 (2005), Bednarek, M. A. et al., Expert Opinion Ther. Patents, 14:327-336 (2004); U.S. Patent No. 6,720,324), memory and memory dysfunction (U.S. Patent No. 6,613,874; Voisey, J. et al., Curr. Drug Targets, 4:586-597 (2003)), modulating pain perception (U.S. Patent 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 treating neuropathic pain (Pontillo, J. et al., Bioorganic &amp; 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 conditions or diseases such as the treatment of renal cachexia (Markison, S. et al., Endocrinology, 146:2766-2773 (2005)) or natriuresis (U.S. Patent No. 6,613,874).

Ligand compounds activating one or more melanocortin receptor would be useful for modulating a wide variety of normalizing or homeostatic activities in a subject in need thereof including thyroxin release (U.S. Patent No. 6,613,874), aldosterone synthesis and release (U.S. Patent No. 6,613,874), body temperature (U.S. Patent No. 6,613,874), blood pressure (U.S. Patent No. 6,613,874), heart rate (U.S. Patent No. 6,613,874), vascular tone (U.S. Patent No. 6,613,874), brain blood flow (U.S. Patent No. 6,613,874), blood glucose levels (U.S. Patent No. 6,613,874), bone metabolism, bone formation or development (Dumont, L. M. et al., Peptides, 26:1929-1935 (2005), ovarian 6 weight (U.S. Patent No. 6,613,874), placental development (U.S. Patent No. 6,613,874), prolactin and FSH secretion (U.S. Patent No. 6,613,874), intrauterine fetal growth (U.S. Patent No. 6,613,874), parturition (U.S. Patent No. 6,613,874), spermatogenesis (U.S. Patent No. 6,613,874), sebum and pheromone secretion (U.S. Patent No. 6,613,874), neuroprotection (U.S. Patent No. 6,639,123) and nerve growth (U.S. Patent No. 6,613,874) as well as modulating motivation (U.S. Patent No. 6,613,874), learning (U.S. Patent No. 6,613,874) and other behaviors (U.S. Patent No. 6,613,874). US 2004/0138136 reports cyclic peptide compositions with a C-terminus free acid and use of these compositions for treatment of sexual dysfunction. WO 2005000339 reports peptide agonists of the melanocortin receptor 4 (MC4) and their uses for treatment of obesity, diabetes mellitus and sexual dysfunction. US 6613874 reports cyclic peptide analogs that exhibit selectivity for the MC-4 and/or the MC-3 receptors relative to other melanocortin receptors;

Kristensen C, et al. (1997) J. Biol. Chem. 272: 12978-12983 reports new insulin analog constructs based on alanine scanning mutagenesis of insulin;

Haskell-Luevano C, et al (1997), J Med Chem 40; 1738-1748 reports results of biological and conformational examination of stereochemical modifications using a template melanotropin peptide, Ac-Nle-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2, on human melanocortin receptors;

Mayer JP, et al (2005), J Med Chem 48: 3095-3098 reports a series of disulfide- constrained human β-melanocyte stimulating hormone (e-MSH)-derived peptides as MC-4R selective agonists;

Hruby V et al (1998), Peptides, Proceedings of the 25th European peptide symposium; Budapest; pp. 70-71 reports the design of potent and selective melanotropin agonist and antagonist ligands for melanocortin 3,4 and 5 receptors;

Hruby V et al (1996), Peptides, Proceedings of the 24th European peptide symposium; Edinburgh; pp. 485-486 reports the design of potent and selective melanotropin agonists and antagonists for the melanocortin 3 and 4 receptors;

Nikiforovich GV, et al (1998), Biopolymers 46:155-167 reports studies of conformational isomerism in α-melanocyte stimulating hormone by the design of cyclic analogues.

It is, therefore, an objective of the present invention to provide ligands for the melanocortin receptors which exhibit greater stability and selectivity for melanocortin receptors than native melanocortin receptor ligands. 7

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to a compound according formula (I): (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1 wherein: A1 is Acc, HN-(CH2)m-C(O), L- or D-amino acid, or deleted; A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or deleted; A4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X1,X2,X3,X4,X5)Phe; A5 is D-Phe, D Nal, D Nal, D-Trp, D-Bal, D-(X1,X2,X3,X4,X5)Phe, L-Phe or D-(Et)Tyr; A6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)n-N(R4R5))-C(O); A7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D Nal, D Nal, D-Bal or D-Bip; A8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2)s-C(O), or deleted; A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A10 is Acc, HN-(CH2)t-C(O), L- or D-amino acid, or deleted; R1 is -OH, or -NH2; each of R2 and R3 is independently for each occurrence selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)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; R4 and R5 each is, independently for each occurrence, H, (C1-C40)alkyl, (C1-C40)heteroalkyl, (C1-C40)acyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, 8 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 is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X1, X2, X3, X4, and X5 each is, independently for each occurrence, H, F, Cl, Br, I, (C1-10)alkyl, substituted (C1-10 )alkyl, (C 2-10)alkenyl, substituted (C2-10)alkenyl, (C2-10)alkynyl, substituted (C2-10)alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN; provided that (I). when R4 is (C1-C40)acyl, aryl(C1-C40)acyl, substituted (C1-C40)acyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl, or -C(NH)-NH2, then R5 is H or (C1-C40)alkyl, (C1-C40)heteroalkyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C2-C40)alkenyl, substituted (C2-C40)alkynyl, or substituted aryl(C1-C40)alkyl; (II). when R2 is (C1-C30)acyl, aryl(C1-C30)acyl, substituted (C1-C30)acyl, or substituted aryl(C1-C30)acyl, then R3 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). either A3 or A8 or both must be present in said compound; (IV). when A2 is 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, Orn, or Lys; (VI). when A8 is Ala or Gly, then A1 is not Nle; and (VII). when A1 is deleted, then R2 and R3 cannot both be H; or a pharmaceutically acceptable salt thereof. A preferred group of compounds of the immediate foregoing formula, is where A1 is A6c, Gaba, Nle, Met, Phe, D-Phe, D Nal, hPhe, Chg, D-Chg, Cha, hCha, hPro, hLeu, Nip, β-hMet, or Oic; 9 A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or deleted; A4 is His; A5 is D-Phe, D Nal, D Nal, D-Trp, D-Bal, or D-(Et)Tyr; A6 is Arg, or hArg; A7 is Trp, Bip, D-Trp, 1-Nal, or 2-Nal; A8 is A6c, Ala, β-Ala, Gaba, Apn, or Ahx; A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys; A10 is Thr, or deleted or a pharmaceutically acceptable salt thereof. A preferred group of compounds of the immediately foregoing group of compounds is where R2 and R3 each is, independently, H, acyl, n-propanoyl, or n-butanoyl or a pharmaceutically acceptable salt thereof. A more preferred compound of formula (I) is where said compound is of the formula: A1 is Acc, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, p-hMet, 2-Nal, D Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val or deleted; A2 is Cys, D-Cys, Pen or Asp; A3 is Gly, Ala, β-Ala, Gaba, Aib, D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or deleted; A4 is His or 3-Pal; A5 is D-Phe, D Nal or D-(Et)Tyr; A6 is Arg or hArg; A7 is Trp, 1-Nal, 2-Nal, Bal, Bip or D-Trp; A8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha or deleted; A9 is Cys, D-Cys, Pen or Lys; A10 is Thr or deleted; wherein at least one of A3 or A8 is deleted, but not both, or a pharmaceutically acceptable salt thereof.

More preferred compounds of the immediately foregoing group of compounds is where said compound is of the formula: 10

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-p-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-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-p-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 Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Cha-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-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 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:8 Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ 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 Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ 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-p-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 11

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: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 ID NO: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-^-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-p-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 ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; SEQ ID NO:14 Ac-Nle-c(Cys-His-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 12

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-p-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 Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-NH2; SEQ ID NO:16 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg 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 Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg 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:19 Ac-Nle-c(Cys-D-Ala-His-D 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:21 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 D-Phe-c(Cys-His-D-Phe-hArg-Trp-p-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-p-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-Arg-Bip-p-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-p-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-p-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 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:28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28 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: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 13

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 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 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 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-His-D Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38

Ac-Nle-c(Asp-His-D Nal-Arg-Trp-p-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Ahx-Cys)-NH2;SEQ ID NO:39 Ac-hPhe-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Cha-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-p-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 14

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-p-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 Nal-Arg-Trp-Cys)-OH; SEQ ID NO:46

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

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

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

Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 or or pharmaceutically acceptable salts thereof.

More preferred of the immediately foregoing group of compounds is a compound of the formula:

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

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

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

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; SEQ ID NO:48 or pharmaceutically acceptable salts thereof. A more preferred compound of formula (I) is where said compound is of the formula: A1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val or deleted; 15 A2 is Cys, Pen or Asp; A3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or deleted; A4 is His or 3-Pal; A5 is D-Phe, D Nal or D-(Et)Tyr; A6 is Arg or hArg; A7 is Trp, 2-Nal, Bal, Bip or D-Trp; A8 is Gly, Ala, β -Ala, Gaba, Apn, Ahx, or deleted; A9 is Cys, D-Cys, Pen or Lys; A10 is Thr or deleted; each of R2 and R3 is independently selected from the group consisting of H or acyl; or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is a compound of the formula:

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-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:27 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp^-Ala-Lys)-NH>; 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^-Ala-D-Cys)-Thr-NH>; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3 16

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-Cha-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-Chg-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-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-p-Ala-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:21 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 D-Phe-c(Cys-His-D-Phe-hArg-Trp-p-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23 D-Phe-c(Cys-His-D-Phe-Arg-Bip-p-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-p-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-p-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28 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: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 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 17

Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34

Ac-Nle-c(Cys-3Pal-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(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16

Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg-Bal-Cys)-NH2; SEQ ID NO:20 Ac-Nle-c(Asp-His-D Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Asp-His-D Nal-Arg-Trp-p-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:39 Ac-hPhe-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Cha-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 or Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 or a pharmaceutically acceptable salt thereof. A more preferred compound of formula (I) is where said compound is of the formula: A1 is Arg, D-Arg, hArg or D-hArg; or a pharmaceutically acceptable salt thereof. A more preferred compound of the immediately foregoing group of compounds is where said compound is of the formula: A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or deleted; A4 is His; A5 is D-Phe, D Nal, D Nal, D-Trp, D-Bal, or D-(Et)Tyr; A6 is Arg, or hArg; A7 is Trp, Bip, D-Trp, 1-Nal, or 2-Nal; A8 is A6c, Ala, β-Ala, Gaba, Apn, or Ahx; A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys; 18 A10 is Thr, or deleted; or a pharmaceutically acceptable salt thereof. A more preferred compound of the immediately foregoing group of compounds is where R2 and R3 each is, independently, H, acyl, n-propanoyl, or n-butanoyl or a pharmaceutically acceptable salt thereof. A more preferred compound of the immediately foregoing group of compounds is where said compound is of the formula: A2 is Cys or Asp; A3 is D-Ala or deleted; A4 is His; A5 is D-Phe or D Nal; A6 is Arg; A7 is Trp; A8 is Ala, Gaba or deleted; A9 is Cys, Pen or Lys; A10 is deleted; or a pharmaceutically acceptable salt thereof. A more preferred compound of the immediately foregoing group of compounds is where R2 and R3 each is, independently, H or acyl; or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is a compound of the formula:

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 or

Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 19 or pharmaceutically acceptable salts thereof.

More preferred of the immediately foregoing group of compounds is a compound of the formula:

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-Pen)-NH2; SEQ ID NO:51 or

Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is a compound of 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.

More preferred of the immediately foregoing group of compounds is a compound of the formula:

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is a compound of the formula:

Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention is directed to a compound according formula (II): (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-NH2 wherein: A1 is Nle or deleted; A2 is Cys or Asp; A3 is Glu or D-Ala; A4 is His; A5 is D-Phe; A6 is Arg; A7 is Trp, 2-Nal or Bal; A8 is Gly, Ala, D-Ala, β-Ala, Gaba or Apn; 20 A9 is Cys or Lys; each of R2 and R3 is independently selected from the group consisting of H or (C1-C6)acyl; provided that (I) . when R2 is (C1-C6)acyl, then R3 is H; and (II) . when A2 is Cys, then A9 is Cys, or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is a compound of the formula:

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-p-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 Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:55 Ac-c(Cys-Glu-His-D-Phe-Arg Nal-Ala-Cys)-NH2; SEQ ID NO:55 Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:56 Ac-c(Cys-D-Ala-His-D-Phe-Arg 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-e-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 or Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2; SEQ ID NO:58 or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula (I) or formula (II) is each of the compounds that are specifically enumerated herein below in the Examples section of the present disclosure, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent, wherein said compound is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or an EC50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:22 or Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49. In yet another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined hereinabove, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent, which is useful for diminishing food intake, decreasing body weight, or a combination thereof, wherein the active ingredient is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:50. In yet another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined hereinabove, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent, which is useful for diminishing food intake, decreasing body weight, or a combination thereof, wherein the active ingredient is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:51. In yet another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined hereinabove, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent, which is useful for diminishing food intake, decreasing body weight, or a combination thereof, wherein the active ingredient is Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49.

In another aspect, the present invention provides a pharmaceutical 24 composition comprising an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent, useful for treating a metabolic disease or medical condition accompanied by weight loss such as anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly. In a further aspect, the disease or condition treated is anorexia. In a further aspect, the disease or condition treated is bulimia. In a further aspect, the disease or condition treated is AIDS wasting or wasting in frail elderly. In a further aspect, the disease or condition treated is cachexia or cancer cachexia.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or 25 formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent, useful for treating a cardiovascular disease or medical condition such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically-acceptable carrier or diluent, useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or for treating alcohol abuse. In a further aspect, the compound of the composition useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or for treating alcohol abuse is a selective melanocortin 4 receptor agonist. In yet a further aspect, the compound of the composition useful for inhibiting alcohol consumption is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC50 at least 15-fold 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. In yet another aspect, the compound of the composition useful for inhibiting alcohol consumption is a selective melanocortin 4 27 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or an EC50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

In another aspect, the present invention provides the use of a therapeutically effective amount of a melanocortin 4 receptor agonist compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or for treating alcohol abuse in a subject in need of such treatment.

In another aspect, the present invention provides a method of eliciting an agonist or an antagonist effect from a melanocortin receptor in a subject in need thereof which comprises administering to said subject an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, wherein said compound is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC50 at 28 least 15- fold 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.

In yet another aspect, the present invention provides a method of eliciting an agonist or an antagonist effect from a melanocortin receptor in a subject in need thereof which comprises administering to said subject an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, wherein said compound is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or an EC50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

In another aspect, the present invention provides a method of treating an acute or chronic inflammatory disease or medical condition such as general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a disease or medical condition with an autoimmune component such as rheumatoid arthritis, gouty arthritis and multiple sclerosis by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a metabolic disease or medical condition accompanied by weight gain such as obesity, feeding disorders and Prader-Willi Syndrome by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a 29 compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof. In a further aspect of the foregoing method, the disease or condition treated is obesity. In yet a further aspect of the foregoing method, the disease or condition treated is a feeding disorder.

In another aspect, the present invention provides a method of decreasing food intake, decreasing body weight or a combination thereof, by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention provides a method of decreasing food intake, decreasing body weight or a combination thereof, by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO:32, 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-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-e-Ala-D-Cys)-Thr-NH2 SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:22, or Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49. In another preferred embodiment, the present invention provides a method of decreasing food intake, decreasing body weight or a combination thereof, by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:50. In another preferred embodiment, the present invention provides a method of decreasing food intake, decreasing body weight or a combination thereof, by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:51. In another preferred embodiment, the present invention provides a method 30 of decreasing food intake, decreasing body weight or a combination thereof, by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49.

In another aspect, the present invention provides a method of decreasing appetite without compromising body weight by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method of decreasing food consumption while increasing body weight by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a metabolic disease or medical condition accompanied by weight loss such as anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof. In a further aspect, the foregoing method is used to treat anorexia. In a further aspect, the foregoing method is used to treat bulimia. In a further aspect, the foregoing method is used to treat AIDS wasting or wasting in frail elderly. In a further aspect, the foregoing method is used to treat cachexia or cancer cachexia.

In another aspect, the present invention provides a method of treating a neoplastic disease or medical condition such as skin cancer and cancer cachexia by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a reproductive or sexual medical condition such as endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females by eliciting an agonist or antagonist effect from a melanocortin receptor by 31 administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a disease or medical condition resulting from treatment or insult to an organism such as organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a cardiovascular disease or medical condition such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a pulmonary disease or medical condition such as acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of enhancing immune tolerance or treating allergies by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating dermatological disease or medical condition such as psoriasis, skin pigmentation depletion, acne and keloid formation by eliciting an agonist or antagonist effect from 32 a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a behavioral or central nervous system or neuronal disease or medical condition such as anxiety, depression, memory dysfunction and neuropathic pain by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating a renal disease or medical condition such as renal cachexia and natriuresis by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of modulating a normalizing or homeostatic activity such as ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of modulating a normalizing or homeostatic activity such as bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or 33 for treating alcohol abuse by eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof. In a further aspect of the foregoing method, the compound is a selective melanocortin 4 receptor agonist. In yet a further aspect of the immediately foregoing method, the compound of the composition useful for inhibiting alcohol consumption is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC50 at least 15- fold 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. In yet another aspect of the foregoing method, the compound of the composition useful for inhibiting alcohol consumption is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, an EC50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or an EC50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

In a further aspect, the present invention provides the use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist compound

according formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat a disease and/or medical condition selected from the group consisting of acute and chronic inflammatory diseases such as general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock; diseases with an autoimmune component such as rheumatoid arthritis, gouty arthritis and multiple sclerosis; metabolic diseases and medical disorders accompanied by weight gain such as obesity, feeding disorders and Prader-Willi Syndrome; metabolic diseases and medical disorders accompanied by weight loss such as anorexia, bulimia, AIDS 34 wasting, cachexia, cancer cachexia and wasting in frail elderly; diabetes, diabetalogical related conditions and complications of diabetes such as retinopathy; neoplastic proliferation such as skin cancer and prostate cancer; reproductive or sexual medical conditions such as endometriosis and uterine bleeding in women, sexual dysfunction, erectile dysfunction and decreased sexual response in females; diseases or conditions resulting from treatment or insult to the organism such as organ transplant rejection, ischemia and reperfusion injury, spinal cord injury and wounding, as well as weight loss caused chemotherapy, radiation therapy, temporary or permanent immobilization or dialysis; cardiovascular diseases or conditions such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia; pulmonary diseases or conditions such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, asthma and pulmonary fibrosis; to enhance immune tolerance and to combat assaults to the immune system such as those associated with certain allergies or organ transplant rejection; treatment of dermatological diseases and conditions such as psoriasis, skin pigmentation depletion, acne, keloid formation and skin cancer; behavioral, central nervous system and neuronal disorders such as anxiety, depression, memory dysfunction, and neuropathic pain; and renal conditions or diseases such as the treatment of renal cachexia and natriuresis.

In a further aspect, the present invention provides the use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist compound according formula (I) or formula (II) as defined hereinabove, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to modulate normalizing or homeostatic activities such as ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain 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. 35

It will be appreciated that therapeutic interventions addressing both normal physiological and pathophysiological processes which utilize the melanocortin receptors are also contemplated.

Additional objects, advantages, and features of the present invention will become apparent from the following description and appended claims, taken in conjunction with the accompanying drawings.

The compounds of formulae (I) or (II) are ligands for at least one of the melanocortin receptors (MC1-R, MC2-R, MC3-R, MC4-R and MC5-R) and a selection thereof were tested for their ability to act as a ligand in the in vitro assay described below. BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1A: Mean difference in food consumed from vehicle in fasted rats 6 hours after administration of 100 nmole/Kg of selected compounds.

Figure 1B. Mean difference in food consumed from vehicle in fasted rats 6 hours after administration of 500 nmole/Kg of selected compounds.

Figure 2A. Cumulative difference in mean food intake from vehicle in rats after administration of various concentrations of Compound A.

Figure 2B. Cumulative mean body weight difference from vehicle in rats after administration of various concentrations of Compound A.

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

Figure 3B. Cumulative mean body weight difference from vehicle in rats after administration of selected compounds.

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

Figure 4B. Cumulative mean body weight difference from vehicle in rats after administration of selected compounds.

DETAILED DESCRIPTION OF THE INVENTION 36

The nomenclature used to define the peptides is that typically used in the art wherein the amino group at the N-terminus appears to the left and the carboxyl group at the C-terminus appears to the right. Where the amino acid has isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Nomenclature and Abbreviations

Symbol Meaning Abu α-aminobutyric acid Ac acyl group Acc 1-amino cyclo(C3-C9)alkyl carboxylic acid A3c 1-amino cyclopropanecarboxylic acid A4c 1-amino cyclobutanecarboxylic acid A5c 1-amino cyclopentanecarboxylic acid A6c 1-amino cyclohexanecarboxylic acid Aha 7-aminoheptanoic acid Ahx 6-aminohexanoic acid Aib α-aminoisobutyric acid Ala or A alanine β-Ala β-alanine Apn 5-aminopentanoic acid (HN-(CH2)4-C(O) Arg or R arginine hArg homoarginine Asn or N asparagine 37

Asp or D

Bal

Bip aspartic acid 3-benzothienylalanine 4,4'-biphenylalanine, represented by the structure

CH2

Bpa 4-Br-Phe

Cha hCha

Chg

Cys or C hCys

Dab

Dap

Dip

Doc 2- Fua Gaba

Gln or Q Glu or E Gly or G

His or H 3- Hyp — NH— CH—C— 4-benzoylphenylalanine 4-bromo-phenylalanine β-cyclohexylalanine homo-cyclohexylalanine cyclohexylglycine cysteine homocysteine 2,4-diaminobutyric acid 2,3-diaminopropionic acid Α,β-diphenylalanine 8-amino-3,6-dioxaoctanoic acid with the structure of: P-(2-furyl)-alanine 4-aminobutyric acid glutamine glutamic acid glycine histidine trans hydroxy-L-proline, carboxylic acid i.e., (2S, 3S) hydroxypyrrolidine 38 4-Hyp 4-hydroxyproline, i.e., (2S, 4R) hydroxypyrrolidine carboxylic acid Ile or I isoleucine Leu or L leucine hLeu homoleucine Lys or K lysine Met or M methionine Λ hMet //-homomethionine 1-Nal /-(l-naphthyl)alanine: 2-Nal /-(2-naphthyl)alanine Nip nipecotic acid Nle norleucine Oic octahydroindole carboxylic acid Orn ornithine 2-Pal /-(2-pyridiyl)alanine 3-Pal /-(3-pyridiyl)alanine 4-Pal /-(4-pyridiyl)alanine Pen penicillamine Phe or F phenylalanine hPhe homophenylalanine Pro or P proline hPro homoproline Ser or S serine Tle tert-Leucine Taz B-(4-thiazolyl) alanine 2-Thi β- (2-thienyl) alanine 3-Thi β- (3-thienyl) alanine Thr or T threonine Trp or W tryptophan Tyr or Y tyrosine D-(Et)Tyr has a structure of 39

Val or V valine

Certain other abbreviations used herein are defined as follows:

Boc: tert-butyloxycarbonyl

Bzl: benzyl DCM: dichloromethane DIC: N, N-diisopropylcarbodiimide DIEA: diisopropylethyl amine

Dmab: 4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene) methylbutyl)- amino} benzyl DMAP: 4-(dimethylamino)pyridine DMF dimethylformamide DNP: 2,4-dinitrophenyl

Fm: fluorenylmethyl

Fmoc: fluorenylmethyloxycarbonyl

For: formyl HBTU: 2-(1H-benzotriazole yl)-1,1,3,3-tetramethyluronium hexafluorophosphate cHex cyclohexyl HOAT: O-(7-azabenzotriazol yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBt: 1-hydroxy-benzotriazole MBHA 4-methylbenzhydrylamine

Mmt: 4-methoxytrityl NMP: N-methylpyrrolidone O-tBu oxy-tert-butyl 40

Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran sulfonyl PyBroP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate tBu: tert-butyl TIS: triisopropylsilane TOS: tosyl Trt trityl TFA: trifluoro acetic acid TFFH: tetramethylfluoroforamidinium hexafluorophosphate Z: benzyloxycarbonyl

Unless otherwise indicated, with the exception of the N-terminal amino acid, all abbreviations (e.g. Ala) of amino acids in this disclosure stand for the structure of -NH-C(R)(R')-CO-, wherein R and R' each is, independently, hydrogen or the side chain of an amino acid (e.g., R = CH3 and R' = H for Ala), or R and R' may be joined to form a ring system.

For the N-terminal amino acid, the abbreviation stands for the structure of:

R', R

-—N

O

The designation "NH2" in e.g., 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-Ala-His-D-Phe-Arg-Trp-Cys)- OH, indicates that the C-terminus is the free acid. -c(Cys-Cys)-“ or “-cyclo(Cys-Cys)-“ denotes the structure: ,S-S.

N

I

HO

N

I

HO 41 “-c(Cys-Pen)-“ or “-cyclo(Cys-Pen)-“ denotes the structure: “-c(Asp-Lys)-“ or “-cyclo(Asp-Lys)-“ denotes the structure:

“Acyl” refers to R”-C(O)-, where R” is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alklyaryl, and is indicated in the general formula of a particular embodiment as “Ac”. "Alkyl" refers to a hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds. The alkyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups. “Hydroxyalkyl” refers to an alkyl group wherein one or more hydrogen atoms of the hydrocarbon group are substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like. "Substituted alkyl" refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with 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 said -C1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, -CF3, -OCH3, -OCF3, and -(CH2)0 COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of -(CH2)0 COOH results in the production of an alkyl acid. Non-limiting examples of alkyl acids containing, or consisting of, -(CH2)0 COOH include 42 2-norbornane acetic acid, tert-butyric acid, 3-cyclopentyl propionic acid, and the like.

The term “halo” encompasses fluoro, chloro, bromo and iodo. "Heteroalkyl" refers to an alkyl wherein one of more of the carbon atoms in the hydrocarbon group is replaced with one or more of the following groups: amino, amido, -O-, -S- or carbonyl. In different embodiments 1 or 2 heteroatoms are present. "Substituted heteroalkyl" refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with 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 said -C1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, -CF3, -OCH3, -OCF3, and -(CH2)0 COOH. In different embodiments 1, 2, 3 or 4 substituents are present. "Alkenyl" refers to a hydrocarbon group made up of two or more carbons where one or more carbon-carbon double bonds are present. The alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups. "Substituted alkenyl" refers to an alkenyl wherein one or more hydrogens are replaced with 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 said -C1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, -CF3, -OCH3, -OCF3, and -(CH2)0 COOH. In different embodiments 1, 2, 3 or 4 substituents are present. "Aryl" refers to an optionally substituted aromatic group with at least one ring having 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 atoms for a heterocyclic aryl are one or more sulfur, oxygen, and/or nitrogen. Non-limiting examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, and the like. Aryl substituents are selected from the group 43 consisting of -C1-20 alkyl, -C1-20 alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NO2, -C1-20 alkyl substituted with halogens, -CF3, -OCF3, and -(CH2)0 COOH. In different embodiments the aryl contains 0, 1, 2, 3, or 4 substituents. "Alkylaryl" refers to an "alkyl" joined to an "aryl".

The term “(C1-C 12)hydrocarbon moiety” encompasses alkyl, alkenyl and alkynyl and in the case of alkenyl and alkynyl there is C2-C12.

As used herein, the term “normalizing” functions or activities refers to those types of functions which may be considered to be involved in normal body function or homeostasis of an organism. Such functions include but are not limited to activities and functions affecting body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels and the like.

As used herein, compounds which are considered to be “selective” for a particular melanocortin receptor are those compounds with a functional activity characterized by an EC50 at least about 2-fold, at least about 5-fold, at least about 10fold, at least about 15-fold, at least about 17-fold, at least about 90-fold, at least about 200-fold, at least about 3000-fold or at least about 10,000-fold, or even greater, selectivity for any melanocortin receptor as compared to any other melanocortin receptor. For example, a selective melanocortin 4 receptor agonist of the invention exhibits a functional activity characterized by an EC50 at least about 15-fold 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, a selective melanocortin 4 receptor agonist of the invention exhibits a functional activity characterized by an EC50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

Synthesis

The peptides of this invention can be prepared by standard solid phase peptide synthesis. See, e.g., Stewart, J.M., et al., Solid Phase Synthesis (Pierce

Chemical Co., 2d ed. 1984). The substituents R2 and R3 of the above generic formula may 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, may be attached 44 using reductive alkylation. Hydroxyalkyl groups, e.g., (C1-C30)hydroxyalkyl, may also be attached using reductive alkylation wherein the free hydroxyl group is protected with a t-butyl ester. Acyl groups, e.g., COE1, may be attached by coupling the free acid, e.g., E1COOH, to the free amine of the N-terminal amino acid by mixing the completed resin with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for one hour. If the free acid contains a free hydroxyl group, e.g., p-hydroxyphenylpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBt.

When R1 is -NH2, the synthesis of the peptide starts with an Fmoc-amino acid which is coupled to the Rink Amide MBHA resin. If R1 is -OH, the synthesis of the peptide starts with a Fmoc-amino acid which is coupled to Wang resin.

In the synthesis of a peptide of this invention containing A6c and/or Aib, the coupling time is 2 hours for these residues and the residue immediately following them.

The following examples describe synthetic methods for making a peptide of this invention, which methods 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 and are not meant to limit the scope of the present invention in any manner.

EXAMPLES

Example 1: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:7

The title peptide was synthesized on an Advanced ChemTech model 396® multiple peptide synthesizer (Louisville, KY 40228) using Fluorenylmethyloxycarbonyl (Fmoc) chemistry. A Rink Amide 4-methylbenzylhydrylamine (MBHA) resin (Novabiochem®, San Diego, CA) with substitution of 0.58 mmol/g was used. The Fmoc amino acids (Novabiochem®, CA and Chem-Impex®, IL) used were Fmoc-Nle-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Ala-OH, Fmoc-His(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-Arg(Pbf)-OH, and Fmoc-Trp(Boc)-OH. The synthesis was carried out on a 0.035 mmol scale. The Fmoc groups were 45 removed by treatment with 25% piperidine in N,N-dimethylformamide (DMF) for 30 minutes. In each coupling step, the Fmoc amino acid (10 eq, 0.35 mmol), N, N-diisopropylcarbodiimide (DIC) (10 eq, 0.35 mmol), and 1-hydroxy-benzotriazole (HOBt) (10 eq, 0.35 mmol) were used in DMF (1.4 mL). After washing with DMF, double-coupling was performed with the Fmoc-amino acid (10 eq, 0.35 mmol), 2-(1-H-benzotriazole yl)-1,1,2,3-tetramethyluronium hexafluorophosphate (HBTU) (8 eq, 0.28 mmol), HOBT (10 eq, 0.35 mmol), and diisopropylethyl amine (DIEA) (20 eq, 0.7 mmol) in DMF (1.26 mL). The ACT 396® multiple peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with DMF, (2) removing Fmoc protecting group with 25% 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 in step 4 in the presence of HBTU, HOBt, and DIEA for 1 hour. The resin was coupled successively according to the sequence of the title peptide. After the peptide chain was assembled and the last Fmoc- protecting group was removed, the resin was washed completely by using DMF and dichloromethane (DCM).

To cleave the title peptide, the resin was treated with a solution (1.5 mL) of TFA, H2O and triisopropylsilane (TIS) (v/v/v: 90/6.2/3.8) for 2 hours at room temperature. The resin was filtered off and the filtrate was poured into 30 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in water (~7 mL) and the pH of the aqueous solution was adjusted to ~7.5 by adding 2N NH4HCO3. The solution was opened to the air for 72 hours at room temperature. The resulting crude product was purified on a reverse-phase preparative HPLC system with a column (4 x 43 cm) of C18 DYNAMAX-100® A0 (Varian®, Walnut Creek, CA). The column was eluted over approximately 1 hour using a linear gradient of 85% A:15% B to 30% A:70% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 10.3 mg (27% yield) of a white solid. Purity was assayed using HPLC and found to be approximately 88%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 1073.6 (in agreement with the calculated 46 molecular weight of 1074.3).

Example 2: Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2 SEQ ID NO:6

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

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 into a 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-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (6 eq, 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 twice with 100% TFA for 2 minutes per treatment, washed with DMF and DCM, and then dried under reduced pressure. One fourth of the peptide-resin (0.05 mmol) was used for the next coupling with Boc-Cha-OH (10 eq, 0.5 mmol) in the presence of HBTU (9 eq, 0.45 mmol) and DIEA (0.25 mL) in DMF for 10 minutes. After the deprotection with 100% TFA in two sessions lasting approximately 2 minutes each, the peptide-resin was then washed with DMF. The final capping step was done by shaking the resin with acetic anhydride (40 eq, 2.0 mmol) and DIEA (20 eq, 1.0 mmol) in DMF for 1 hour. After washing with DMF, the resin was treated twice with a solution of 20% mercaptoethanol/10% DIEA in DMF, each treatment lasting approximately 30 minutes, to remove the DNP group on 47 the Histidine side chain. The formyl group on the side chain of Tryptophan was removed by shaking with a solution of 15% ethanolamine/ 15% water/ 70% DMF twice for 30 minutes per shaking. The peptide-resin was washed with DMF and DCM and dried under reduced pressure. The final cleavage was done by stirring the peptide-resin in 10 mL of HF containing 1 mL of anisole and dithiothreitol (30 mg) at 0°C for 75 minutes. HF was removed by a flow of nitrogen. The residue was washed with ether (6 x 10 mL) and extracted with 4N HOAc (6 x 10 mL).

The peptide mixture in the aqueous extract was purified on reverse-phase preparative high pressure liquid chromatography (HPLC) using a reverse phase VYDAC® C18 column (Nest Group®, Southborough, MA). The column was eluted with a linear gradient (10% to 50% of 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% of TFA). Fractions were collected and checked on analytical HPLC. Those containing pure product were combined and lyophilized to dryness. 5.1 mg of a white solid was obtained. Yield was 8.9%. Purity was 94.5% based on analytical HPLC analysis. Electro-spray mass spectrometer (MS(ES))S analysis gave the molecular weight at 1148.5 (in agreement with the calculated molecular weight of 1148.3).

Other peptides of the invention can be prepared by a person of ordinary skill in the art using synthetic procedures analogous to those disclosed generally hereinabove and/or to those disclosed specifically in the foregoing examples, as were the compounds depicted in Tables 1A and 1B.

The following examples can be made according to the appropriate procedures described above:

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-p-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 48 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-p-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 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:8 Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ 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 Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ 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-p-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:11 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 49

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 ID NO: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^-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^-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 ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; SEQ ID NO:14 Ac-Nle-c(Cys-His-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^-Ala-Cys)-NH>; 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 Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-NH2; SEQ ID NO:16 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg Nal-Cys)-NH2; SEQ ID NO:17 50 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 Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg 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:19 Ac-Nle-c(Cys-D-Ala-His-D 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:21 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 D-Phe-c(Cys-His-D-Phe-hArg-Trp^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-Arg-Bip£-Ala-D-Cys)-Thr-NH>; SEQ ID NO:25 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-hArg-Bip^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip^-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^-Ala-Cys)-NH>; 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: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 Nal-Ala-Cys)-NH2; SEQ ID NO:55 Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:56 Ac-c(Cys-D-Ala-His-D-Phe-Arg 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-e-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 51

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: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 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 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 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 Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Asp-His-D Nal-Arg-Trp^-Ala-Lys)-NH>; SEQ ID NO:38 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Ahx-Cys)-NH2;SEQ ID NO:39 Ac-hPhe-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Cha-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Nle-c(Asp-His-D-Phe-Arg-TrpT-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 52 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-p-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 Nal-Arg-Trp-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg-Bal-Cys)-OH; SEQ ID NO:46 Ac-Nle-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 Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 and 53

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

Table 1A

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: Ac-Nle-c(Asp-His-D-Phe-Arg- Trp-p-Ala-Lys)-NH2 1095.27 1095.2 96.4 SEQ ID NO:1 Ac-Nle-c(Asp-His-D-Phe-Arg- Trp-A6c-Lys)-NH2 1149.36 1149.05 96 SEQ ID NO:1 Ac-Nle-c(Cys-His-D-Phe-Arg- Trp-Ahx-Cys)-NH2 1116.38 1115.8 98 SEQ ID NO:2 D-Phe-c(Cys-His-D-Phe-Arg- Trp-Ala-D-Cys)-Thr-NH2 1167.38 1167.3 99 SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg- Trp-p-Ala-D-Cys)-Thr-NH2 1167.38 1167.5 93 SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg- Trp-Gaba-D-Cys)-Thr-NH2 1181.41 1181.9 99 SEQ ID NO:3 Ac-Nle-c(Cys-His-D-Phe-Arg- Trp-Apn-Cys)-NH2 1102.35 1103 99 SEQ ID NO:2 Ac-Nle-c(Asp-His-D-Phe-Arg- Trp-Apn-Lys)-NH2 1123.32 1123.9 99 SEQ ID NO:4 Ac-A6c-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1121.31 1121.2 93 SEQ ID NO:5 Ac-D Nal-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 1193.37 1193.2 92.6 SEQ ID NO:6 Ac-Cha-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2; 1149.36 1149.4 94.5 SEQ ID NO:6 Ac-Nle-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1109.3 1109.2 91.5 SEQ ID NO:6 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 1074.3 1074.6 98.3 SEQ ID NO:7 Ac-Nle-c(Cys-e-Ala-His-D-Phe- Arg-Trp-Cys)-NH2 1074.3 1074.4 91 SEQ ID NO:7 54

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: Ac-Nle-c(Cys-Gaba-His-D-Phe- Arg-Trp-Cys)-NH2 1088.32 1088.4 93 SEQ ID NO:7 Ac-Nle-c(Cys-Aib-His-D-Phe- Arg-Trp-Cys)-NH2 1088.32 1088.4 80 SEQ ID NO:7 Ac-Nle-c(Cys-Gly-His-D-Phe- Arg-Trp-Cys)-NH2 1060.27 1060.4 90 SEQ ID NO:7 Ac-Nle-c(D-Cys-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 1074.3 1074.4 93 SEQ ID NO:8 Ac-Nle-c(D-Cys-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 1074.3 1074.4 81 SEQ ID NO:8 Ac-Nle-c(D-Cys-e-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 1074.3 1074.4 92 SEQ ID NO:8 Ac-Nle-c(D-Cys-Gaba-His-D- Phe-Arg-Trp-Cys)-NH2 1088.32 1088.4 94 SEQ ID NO:8 Ac-Nle-c(D-Cys-Aib-His-D- Phe-Arg-Trp-Cys)-NH2 1088.32 1088.4 91 SEQ ID NO:8 Ac-Nle-c(D-Cys-Gly-His-D- Phe-Arg-Trp-Cys)-NH2 1060.27 1060.4 96 SEQ ID NO:8 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-D-Cys)-NH2 1074.3 1074.4 66 SEQ ID NO:9 Ac-Nle-c(Cys-e-Ala-His-D-Phe- Arg-Trp-D-Cys)-NH2 1074.3 1074.2 94 SEQ ID NO:9 Ac-Nle-c(Cys-Gaba-His-D-Phe- Arg-Trp-D-Cys)-NH2 1088.32 1088.2 93 SEQ ID NO:9 Ac-Nle-c(Cys-Aib-His-D-Phe- Arg-Trp-D-Cys)-NH2 1088.32 1088.4 90 SEQ ID NO:9 Ac-Nle-c(Cys-Gly-His-D-Phe- Arg-Trp-D-Cys)-NH2 1060.27 1060.4 91 SEQ ID NO:9 Ac-Nle-c(D-Cys-Ala-His-D- Phe-Arg-Trp-D-Cys)-NH2 1074.3 1074.4 65 SEQ ID NO:10 Ac-Nle-c(D-Cys-D-Ala-His-D- Phe-Arg-Trp-D-Cys)-NH2 1074.3 1074.2 93 SEQ ID NO:10 Ac-Nle-c(D-Cys-e-Ala-His-D- Phe-Arg-Trp-D-Cys)-NH2 1074.3 1074.4 92 SEQ ID NO:10 Ac-Nle-c(D-Cys-Gaba-His-D- Phe-Arg-Trp-D-Cys)-NH2 1088.32 1088.4 90 SEQ ID NO:10 Ac-Nle-c(D-Cys-Aib-His-D- Phe-Arg-Trp-D-Cys)-NH2 1088.32 1088 95 SEQ ID NO:10 Ac-Oic-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1147.35 1147.4 97.5 SEQ ID NO:11 Ac-Chg-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1135.33 1135.1 99 SEQ ID NO:11 55

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: Ac-hCha-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1163.39 1163.4 99 SEQ ID NO:11 Ac-D-Cha-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 1149.36 1149.2 99 SEQ ID NO:11 Ac-Nip-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1107.28 1107 98.9 SEQ ID NO:11 Ac-hPro-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1107.28 1107.4 99 SEQ ID NO:11 Ac-hLeu-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1123.32 1123.2 99 SEQ ID NO:11 Ac-D-hCha-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 1163.39 1163.6 94 SEQ ID NO:59 Ac-Phe-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1143.31 1143.3 96.9 SEQ ID NO:11 Ac-D-Phe-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 1143.31 1143.3 96.5 SEQ ID NO:11 Ac-D-Chg-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 1135.33 1135.4 99 SEQ ID NO:11 n-Butyryl-Cha-c(Asp-His-D- Phe-Arg-Trp-Gaba-Lys)-NH2 1177.41 1177.5 88.6 SEQ ID NO:60 Ac-hPhe-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1157.34 1157.2 70 SEQ ID NO:11 Ac-e-hMet-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 1141.36 1141.2 89 SEQ ID NO:11 Ac-Gaba-c(Asp-His-D-Phe-Arg- Trp-Gaba-Lys)-NH2 1081.24 1080.9 92.5 SEQ ID NO:11 Ac-Cha-c(Asp-His-D-Phe-Arg- D-Trp-Ala-Lys)-NH2 1135.33 1135.2 85 SEQ ID NO:13 Ac-hCha-c(Asp-His-D-Phe-Arg- D-Trp-Ala-Lys)-NH2 1149.36 1149.1 87 SEQ ID NO:13 Ac-Leu-c(Asp-His-D-Phe-Arg- D-Trp-Ala-Lys)-NH2 1095.27 1095.4 98.6 SEQ ID NO:13 Ac-hLeu-c(Asp-His-D-Phe-Arg- D-Trp-Ala-Lys)-NH2 1109.3 1109.2 93.8 SEQ ID NO:13 Ac-Phe-c(Asp-His-D-Phe-Arg- D-Trp-Ala-Lys)-NH2 1129.29 1129.2 81.9 SEQ ID NO:13 Ac-Nle-c(Asp-His-D-Phe-Arg- D-Trp-D-Ala-Lys)-NH2 1095.27 1095.3 97 SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg- D-Trp-e-Ala-Lys)-NH2 1095.27 1095.3 82 SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg- D-Trp-Gaba-Lys)-NH2 1109.3 1109.1 99 SEQ ID NO:14 56

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: Ac-Nle-c(Asp-His-D-Phe-Arg- D-Trp-Aha-Lys)-NH2 1137.35 1137.4 98 SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg- D-Trp-Apn-Lys)-NH2 1123.32 1123.3 97.3 SEQ ID NO:14 Ac-Nle-c(Cys-His-D-Phe-Arg- D-Trp-Apn-Cys)-NH2 1102.35 1102 99 SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg- D-Trp-Gaba-Cys)-NH2 1088.32 1087.8 97 SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg- D-Trp-Ahx-Cys)-NH2 1116.38 1116.2 99 SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg- D-Trp-j3-Ala-Cys)-NH2 1074.3 1073.8 99.9 SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg- D-Trp-D-Ala-Cys)-NH2 1074.3 1073.8 99.9 SEQ ID NO:15 Ac-Nle-c(Cys-D-Ala-His-D N al-Arg-T rp-Cys)-NH2 1124.36 1123.6 96.1 SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-NH2 1135.38 1134.5 99.1 SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg Nal-Cys)-NH2 1135.38 1134.6 94.8 SEQ ID NO:16 nButanoyl-Nle-c(Cys-D-Ala- His-D-Phe-Arg Nal-Cys)-NH2 1113.37 1112.6 95.7 SEQ ID NO:17 nButanoyl-Nle-c(Cys-D-Ala- His-D-Phe-Arg-Trp-Cys)-NH2 1102.35 1101.5 99.9 SEQ ID NO:17 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg Nal-Cys)-NH2 1085.32 1084.4 97.7 SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg- 1-N al-Cys)-NH2 1085.32 1084.5 96.6 SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Bal-Cys)-NH2 1091.35 1090.4 96.2 SEQ ID NO:18 Ac-Nle-c(Cys-D-Glu-His-D- Phe-Arg-Trp-Cys)-NH2 1132.33 1131.5 99.9 SEQ ID NO:61 Ac-Nle-c(Asp-His-D-Phe-Arg- Trp-D-Ala-Lys)-NH2 1095.27 1094.6 99.9 SEQ ID NO:19 Ac-Nle-c(Cys-D-Ala-His-D Nal-Arg-Bal-Cys)-NH2 1141.41 1140.5 95.6 SEQ ID NO:20 Ac-Nle-c(Pen-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 1102.35 1101.6 99.9 SEQ ID NO:21 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Pen)-NH2 1102.35 1101.6 99.9 SEQ ID NO:22 Ac-Nle-c(Pen-D-Ala-His-D- Phe-Arg-Trp-Pen)-NH2 1130.4 1129.6 99.9 SEQ ID NO:22 57

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: D-Phe-c(Cys-His-D-Phe-hArg- Trp-e-Ala-D-Cys)-Thr-NH2 1181.41 1181.7 96.9 SEQ ID NO:23 D-Phe-c(Cys-His-D-(Et)Tyr- Arg-Trp-e-Ala-D-Cys)-Thr-NH2 1211.43 1211.7 97.1 SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-Arg- Bip-e-Ala-D-Cys)-Thr-NH2 1204.44 1204.6 99 SEQ ID NO:25 D-Phe-c(Cys-His-D-(Et)Tyr-hArg- Trp-e-Ala-D-Cys)-Thr-NH2 1225.46 1225.7 97 SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-hArg- Bip-e-Ala-D-Cys)-Thr-NH2 1218.47 1218.8 99 SEQ ID NO:26 D-Phe-c(Cys-His-D-(Et)Tyr-hArg- Bip-e-Ala-D-Cys)-Thr-NH2 1262.52 1263 99 SEQ ID NO:26 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Gly-Cys)-NH2 1131.35 1131.2 96.8 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-D-Ala-Cys)-NH2 1145.37 1145.3 96.4 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-T rp- e-Ala-Cys)-NH2 1145.37 1145.2 98.2 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Gaba-Cys)-NH2 1159.4 1159.2 95.1 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-T rp-Apn-Cys)-NH2 1173.43 1173.3 96.8 SEQ ID NO:54 Nle-c(Cys-His-D-Phe-Arg-Trp- Apn-Cys)-NH2 1060.31 1060.3 98.5 SEQ ID NO:27 Ac-Nle-c(Asp-D-Ala-His-D- Phe-Arg-Trp-Lys)-NH2 1095.27 1094.7 96.2 SEQ ID NO:28 Ac-Nle-c(Asp-D-Ala-His-D- Phe-Arg-Bal-Lys)-NH2 1112.32 1111.7 96.5 SEQ ID NO:28 Ac-c(Cys-Glu-His-D-Phe-Arg- Trp-Ala-Cys)-NH2 1090.25 1089.6 99.9 SEQ ID NO:55 Ac-c(Cys-Glu-His-D-Phe-Arg Nal-Ala-Cys)-NH2 1101.27 1100.6 98.3 SEQ ID NO:55 Ac-c(Cys-D-Ala-His-D-Phe- Arg-Trp-Ala-Cys)-NH2 1032.22 1031.5 95.2 SEQ ID NO:56 Ac-c(Cys-D-Ala-His-D-Phe- Arg Nal-Ala-Cys)-NH2 1043.24 1042.5 95.6 SEQ ID NO:56 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Ala-Cys)-NH2 1144.39 1144.6 95.3 SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-T rp- e-Ala-Cys)-NH2 1145.37 1144.6 97.3 SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Gaba-Cys)-NH2 1158.41 1158.6 96.5 SEQ ID NO:57 58

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Pen)-OH 1103.33 1103 99.9 SEQ ID NO:29 Ac-Nle-c(Cys-D-Abu-His-D- Phe-Arg-Trp-Cys)-NH2 1088.32 1087.6 99.9 SEQ ID NO:30 Ac-Nle-c(Cys-D-V al-His-D-Phe-Arg-Trp-Cys)-NH2 1102.35 1101.7 99.9 SEQ ID NO:30 Ac-Nle-c(Cys-D-Ile-His-D-Phe- Arg-Trp-Cys)-NH2 1116.38 1115.7 99.9 SEQ ID NO:30 Ac-Nle-c(Cys-D-Leu-His-D- Phe-Arg-Trp-Cys)-NH2 1116.38 1115.8 97.4 SEQ ID NO:30 Ac-Nle-c(Cys-D-Tle-His-D-Phe- Arg-Trp-Cys)-NH2 1116.38 1115.5 96.5 SEQ ID NO:30 Ac-Nle-c(Cys-D-Cha-His-D- Phe-Arg-Trp-Cys)-NH2 1156.44 1155.6 96.4 SEQ ID NO:30 Ac-Nle-c(Pen-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 1116.38 1115.7 95 SEQ ID NO:31 Ac-Nle-c(Cys-His-D-Phe-Arg- Trp-Gaba-Pen)-NH2 1116.38 1115.5 99.9 SEQ ID NO:32 Ac-Nle-c(Pen-His-D-Phe-Arg- Trp-Gaba-Pen)-NH2 1144.43 1144 99.9 SEQ ID NO:32 Ac-Leu-c(Cys-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 1088.32 1088 96.7 SEQ ID NO:33 Ac-Cha-c(Cys-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 1128.39 1128.4 95.8 SEQ ID NO:33 Ac-Ile-c(Cys-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 1088.32 1088.4 95 SEQ ID NO:33 Ac-Phe-c(Cys-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 1122.34 1122 95.2 SEQ ID NO:33 Ac-V al-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2 1074.3 1074.6 95.4 SEQ ID NO:33 Ac Nal-c(Cys-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 1172.4 1172.2 95.2 SEQ ID NO:33 Nle-c(Cys-His-D-Phe-Arg-Trp- Gaba-Cys)-NH2 1046.29 1046.4 97.6 SEQ ID NO:34 Phe-c(Cys-His-D-Phe-Arg-Trp- Gaba-Cys)-NH2 1080.3 1080 95.8 SEQ ID NO:34 Ac-Nle-c(Cys Pal-D-Phe-Arg- Trp-Gaba-Cys)-NH2 1099.35 1099.6 96.6 SEQ ID NO:35 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-T rp-Cys)-OH 1075.28 1075.2 99.9 SEQ ID NO:36 Ac-Nle-c(Cys-His-Phe-Arg-D- Trp-Gaba-Cys)-NH2 1088.32 1088 95.8 SEQ ID NO:37 59

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: Ac-Nle-c(Asp-D-Ala-His-D- Phe-Arg-Bal-Ala-Lys)-NH2 1183.4 1182.85 99.9 SEQ ID NO:58 Ac-Nle-c(Asp-His-D Nal- Arg-Trp-Ala-Lys)-NH2 1145.33 1145 99.99 SEQ ID NO:38 Ac-Nle-c(Asp-His-D Nal- Arg-Trp-pAla-Lys)-NH2 1145.33 1145 99.99 SEQ ID NO:38 Ac-Nle-c(Cys-His-D Nal-Arg- Trp-Gaba-Cys)-NH2 1138.38 1137.8 99.99 SEQ ID NO:39 Ac-Nle-c(Cys-His-D Nal-Arg- Trp-Ahx-Cys)-NH2 1166.44 1166 99 SEQ ID NO:39 Ac-hPhe-c(Asp-His-D Nal- Arg-Trp-Gaba-Lys)-NH2 1207.4 1206.9 99 SEQ ID NO:40 Ac-Cha-c(Asp-His-D N al-Arg-Trp-Gaba-Lys)-NH2 1199.42 1198.8 100 SEQ ID NO:40 Ac-Arg-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 1117.3 1116.9 95.10 SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 1117.33 1116.8 99.2 SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Pen)-NH2 1145.38 1144.9 96.4 SEQ ID NO:51 Ac-D-Arg-c(Cys-His-D-Phe- Arg-Trp-Gaba-Pen)-NH2 1159.41 1158.9 99.9 SEQ ID NO:52 Ac-Arg-c(Cys-His-D-Phe-Arg- Trp-Gaba-Pen)-NH2 1159.41 1159.1 99 SEQ ID NO:52 Ac-Arg-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Pen)-NH2 1145.38 1145.1 99 SEQ ID NO:51 Ac-D-Arg-c(Asp-His-D-Phe- Arg-Trp-Ala-Lys)-NH2 1138.3 1138.0 98.0 SEQ ID NO:53 Ac-Arg-c(Asp-His-D-Phe-Arg- Trp-Ala-Lys)-NH2 1138.3 1138.1 99.0 SEQ ID NO:53

Table 1B

Compound Calculated Molecular Weight Experimental Molecular Weight Purity SEQ ID NO: Ac-Arg-c(Cys-D-Ala-His-D N al-Arg-T rp-Cys)-NH2 1167.39 1167.40 99.9 SEQ ID NO:49 60

Example 3: In vitro studies

Compounds of the present invention can be and were tested for activity as ligands of one or more of the melanocortin receptors according to the following procedures. One skilled in the art would know that procedures similar to those described herein may be used to assay the binding activities of the compounds of the invention to melanocortin receptor molecules.

Radioligand Binding Assays

Cellular membranes used for the in vitro receptor binding assays were obtained from transgenic CHO-K1 cells stably expressing hMC-R receptor subtypes 1, 3, 4 or 5. The CHO-K1 cells expressing the desired hMC-R receptor type were sonicated (Branson® setting 7, approximately 30 sec) in ice-cold 50 mM Tris-HCl at pH 7.4 and then centrifuged at 39,000 g for 10 minutes at approximately 4°C. The pellets were resuspended in the same buffer and centrifuged at 50,000 g for 10 minutes at approximately 4°C. The washed pellets containing the cellular membranes were stored at approximately - 80°C.

Competitive inhibition of [125I](Tyr2)-(Nle4-D-Phe7)a-MSH ([125I]-NDP-a-MSH, Amersham Biosciences®) binding was carried out in polypropylene 96 well plates. Cell membranes (1-10 μg protein/well) prepared as described above were incubated in 50 mM Tris-HCl at pH 7.4 containing 0.2% bovine serum albumin (BSA), 5 mM MgCl2, 1 mM CaCl2 and 0.1 mg/mL bacitracin, with increasing concentrations of the test compound and 0.1-0.3 nM [125I]-NDP-a-MSH for approximately 90-120 minutes at approximately 37°C. Bound [125I]-NDP-a-MSH ligand was separated from free [125I]-NDP-a-MSH by filtration through GF/C glass fiber filter plates (Unifilter®; Packard) presoaked with 0.1 % (w/v) polyethylenimine (PEI), using a Packard Filtermate® harvester. Filters were washed three times with 50 mM Tris-HCl at pH 7.4 at a temperature of approximately 0-4°C and then assayed for radioactivity using a Packard Topcount® scintillation counter. Binding data were analyzed by computer-assisted non-linear regression analysis (XL fit; IDBS). 61 A selection of the preferred embodiments was tested using the abovediscussed assay and the binding constants (Ki in nM) are reported in Tables 2A, 2B and 2C. TABLES 2A, 2B and 2C - Radioligand Binding Assay Data for Selected Compounds

Table 2A

Compound Ki hMC 1-R Ki hMC 3-R Ki hMC4- R Ki hMC5- R Ki hMC1-R/ MC4-R SEQ ID NO: Ac-Arg-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 3.87 10.1 2.09 430 1.9 SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His- D-Phe-Arg-Trp-Cys)-NH2 4.01 12.1 1.76 352 2.3 SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His- D-Phe-Arg-Trp-Pen)-NH2 8.29 13.3 2.78 816 3.0 SEQ ID NO:51 Ac-D-Arg-c(Cys-His-D-Phe- Arg-Trp-Gaba-Pen)-NH2 3.93 172 11.0 538 0.36 SEQ ID NO:52 Ac-Arg-c(Cys-His-D-Phe- Arg-Trp-Gaba-Pen)-NH2 1.81 20.5 4.57 502 0.4 SEQ ID NO:52 Ac-Arg-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Pen)-NH2 9.67 22.0 4.2 1900 2.3 SEQ ID NO:51 Ac-D-Arg-c(Asp-His-D- Phe-Arg-Trp-Ala-Lys)-NH2 0.79 45.5 1.21 493 0.6 SEQ ID NO:53 Ac-Arg-c(Asp-His-D-Phe- Arg-Trp-Ala-Lys)-NH2 0.68 20.7 1.01 783 0.7 SEQ ID NO:53

Table 2B

Compound Ki hMC1- R Ki hMC 3-R Ki hMC4- R Ki hMC 5-R Ki hMC1-R /MC4-R SEQ ID NO: Ac-Nle-c(Cys-D-Ala-His-D- 2-Nal-Arg Nal-Cys)-NH2 114 63.9 3.07 1657 37.1 SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 11 26 7.6 1800 1.4 SEQ ID NO:7 D-Phe-c(Cys-His-D-(Et)Tyr- Arg-Trp^-Ala-D-Cys)-Thr- NH2 0.05 9.3 1.1 2.9 0.0 SEQ ID NO:24 Nle-c(Cys-His-D-Phe-Arg- Trp-Apn-Cys)-NH2 0.07 4.1 0.85 8.8 0.1 SEQ ID NO:27 Ac-Nle-c(Cys-His-D-Phe- Arg-Trp-Gaba-Pen)-NH2 0.12 10 0.43 0.42 0.3 SEQ ID NO:32 62

Compound Ki hMC1- R Ki hMC 3-R Ki hMC4- R Ki hMC 5-R Ki hMC1-R /MC4-R SEQ ID NO: Nle-c(Cys-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 0.05 1.3 0.47 0.2 0.1 SEQ ID NO:34 Ac-Nle-c(Asp-His-D-Phe- Arg-Trp^-Ala-Lys)-NH2 0.0996 9318 0.617 10.9 0.16 SEQ ID NO:1 Ac-Nle-c(Cys-His-D-Phe- Arg-Trp-Ahx-Cys)-NH2 .0132 16.1 1.23 0.359 0.11 SEQ ID NO:2 D-Phe-c(Cys-His-D-Phe-Arg- Trp^-Ala-D-Cys)-Thr-NH2 0.207 43.2 2.58 344 0.08 SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg- Trp-Gaba-D-Cys)-Thr-NH2 0.420 106 4.75 1260 0.09 SEQ ID NO:3 Ac-Nle-c(Cys-His-D-Phe- Arg-Trp-Apn-Cys)-NH2 0.0951 9.33 0.894 13.4 0.11 SEQ ID NO:2 Ac-Nle-c(Asp-His-D-Phe- Arg-Trp-Apn-Lys)-NH2 0.999 300 11.1 431 0.09 SEQ ID NO:4 Ac-Cha-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 0.106 11.8 1.49 110 0.07 SEQ ID NO:6 Ac-Nle-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 0.0506 9.89 1.04 16.3 0.05 SEQ ID NO:6 Ac-Chg-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 0.884 223 22.5 609 0.04 SEQ ID NO:11 Ac-hCha-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 0.721 93.5 56.0 747 0.01 SEQ ID NO:11 Ac-D-Chg-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 0.227 14.5 2.99 164 0.08 SEQ ID NO:11 Ac-hPhe-c(Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2 0.277 25.2 3.37 203 0.08 SEQ ID NO:11 Ac-Nle-c(Cys-His-D-Phe- Arg-D-Trp^-Ala-Cys)-NH2 0.323 14.1 1.96 24.0 0.16 SEQ ID NO:15 Ac-Nle-c(Pen-D-Ala-His-D- Phe-Arg-Trp-Cys)-NH2 34.1 118 17.0 5560 2.01 SEQ ID NO:21 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Pen)-NH2 29.1 22.8 3.84 2550 7.58 SEQ ID NO:22 D-Phe-c(Cys-His-D-Phe-hArg- Trp^-Ala-D-Cys)-Thr-NH2 0.442 123 10.3 521 0.04 SEQ ID NO:23 D-Phe-c(Cys-His-D-Phe-Arg- Bip^-Ala-D-Cys)-Thr-NH2 5.80 3370 583 1130 0.01 SEQ ID NO:25 D-Phe-c(Cys-His-D-(Et)Tyr- hArg-Trp^-Ala-D-Cys)-Thr- NH2 0.0567 31.4 14.7 9.27 0 SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-hArg- Bip^-Ala-D-Cys)-Thr-NH2 1.68 1260 172 1220 0.01 SEQ ID NO:26 63

Compound Ki hMC1- R Ki hMC 3-R Ki hMC4- R Ki hMC 5-R Ki hMC1-R /MC4-R SEQ ID NO: D-Phe-c(Cys-His-D-(Et)Tyr- hArg-Bip-p-Ala-D-Cys)-Thr- NH2 0.128 85.6 36.9 38.0 0 SEQ ID NO:26 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Gly-Cys)-NH2 0.352 149 3.01 339 0.12 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-D-Ala-Cys)-NH2 3.93 876 48.0 4940 0.08 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-p-Ala-Cys)- NH2 0.995 287 4.80 766 0.21 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Gaba-Cys)-NH2 0.848 184 3.76 956 0.23 SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Apn-Cys)-NH2 1.10 228 7.58 859 0.15 SEQ ID NO:54 Ac-Nle-c(Asp-D-Ala-His-D- Phe-Arg-Trp-Lys)-NH2 0.659 98.9 2.55 4.19 0.26 SEQ ID NO:28 Ac-Nle-c(Asp-D-Ala-His-D- Phe-Arg-Bal-Lys)-NH2 4.12 445 50.6 4300 0.08 SEQ ID NO:28 Ac-c(Cys-Glu-His-D-Phe- Arg-Trp-Ala-Cys)-NH2 111 1710 47.7 694 2.33 SEQ ID NO:55 Ac-c(Cys-Glu-His-D-Phe- Arg Nal-Ala-Cys)-NH2 262 2500 96.4 1460 2.72 SEQ ID NO:55 Ac-c(Cys-D-Ala-His-D-Phe- Arg-Trp-Ala-Cys)-NH2 199 5990 96.7 > 10000 2.06 SEQ ID NO:56 Ac-c(Cys-D-Ala-His-D-Phe- Arg Nal-Ala-Cys)-NH2 132 4560 40.7 8810 3.24 SEQ ID NO:56 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Ala-Cys)-NH2 9.12 1130 22.1 2860 0.41 SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-p-Ala-Cys)-NH2 1.00 227 5.55 496 0.18 SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Gaba-Cys)-NH2 0.536 169 3.12 358 0.17 SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D- Phe-Arg-Trp-Pen)-OH 32.1 330 17.4 165 1.84 SEQ ID NO:29 Ac-Nle-c(Cys-D-Abu-His- D-Phe-Arg-Trp-Cys)-NH2 10.6 41.1 7.69 54.9 1.38 SEQ ID NO:30 Ac-Nle-c(Cys-D-Val-His-D- Phe-Arg-Trp-Cys)-NH2 13.0 104 10.1 40 1.29 SEQ ID NO:30 Ac-Nle-c(Cys-D-Ile-His-D- Phe-Arg-Trp-Cys)-NH2 4.28 38.5 9.0 12.5 0.48 SEQ ID NO:30 Ac-Nle-c(Cys-D-Leu-His-D- Phe-Arg-Trp-Cys)-NH2 1.60 6.82 4.13 5.57 0.39 SEQ ID NO:30 64

Compound Ki hMC1- R Ki hMC 3-R Ki hMC4- R Ki hMC 5-R Ki hMC1-R /MC4-R SEQ ID NO: Ac-Nle-c(Cys-D-Tle-His-D- Phe-Arg-Trp-Cys)-NH2 12.0 85.8 11.2 40 1.07 SEQ ID NO:30 Ac-Nle-c(Cys-D-Cha-His-D- Phe-Arg-Trp-Cys)-NH2 0.353 2.08 1.41 0.857 0.25 SEQ ID NO:30 Ac-Nle-c(Pen-His-D-Phe- Arg-Trp-Gaba-Cys)-NH2 0.537 86.1 5.89 2.56 0.09 SEQ ID NO:31 Ac-Nle-c(Pen-His-D-Phe- Arg-Trp-Gaba-Pen)-NH2 0.744 178 3.51 2.69 0.21 SEQ ID NO:32 Ac-Leu-c(Cys-His-D-Phe- Arg-Trp-Gaba-Cys)-NH2 0.216 17.4 0.995 0.486 0.22 SEQ ID NO:33 Ac-Cha-c(Cys-His-D-Phe- Arg-Trp-Gaba-Cys)-NH2 0.107 9.11 0.884 0.354 0.12 SEQ ID NO:33 Ac-Ile-c(Cys-His-D-Phe- Arg-Trp-Gaba-Cys)-NH2 0.148 13.9 1.06 0.423 0.14 SEQ ID NO:33 Ac-Phe-c(Cys-His-D-Phe- Arg-Trp-Gaba-Cys)-NH2 0.254 18.5 2.13 0.714 0.12 SEQ ID NO:33 Ac-V al-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2 0.256 29.9 1.98 0.864 0.13 SEQ ID NO:33 Ac Nal-c(Cys-His-D-Phe- Arg-Trp-Gaba-Cys)-NH2 0.560 39.2 2.94 2.73 0.19 SEQ ID NO:33 Phe-c(Cys-His-D-Phe-Arg- Trp-Gaba-Cys)-NH2 0.186 15.2 4.93 0.537 0.04 SEQ ID NO:34 Ac-Nle-c(Cys Pal-D-Phe- Arg-Trp-Gaba-Cys)-NH2 21.1 151 10.4 92.6 2.03 SEQ ID NO:35 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-T rp-Cys)-OH 30.7 152 15.6 114 1.97 SEQ ID NO:36 Ac-Nle-c(Cys-His-Phe-Arg- D-Trp-Gaba-Cys)-NH2 5.20 150 138 20.3 0.04 SEQ ID NO:37 Ac-Nle-c(Asp-D-Ala-His-D- Phe-Arg-Bal-Ala-Lys)-NH2 4.89 290 21.3 11.1 0.23 SEQ ID NO:58 Ac-Nle-c(Cys-D-Ala-His-D- 2-Nal-Arg-Trp-Cys)-NH2 25.5 3.82 7.61 102 3.35 SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D- 2-Nal-Arg Nal-Cys)-NH2 32.5 5.85 2.53 94.6 12.85 SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D- 2-Nal-Arg-Bal-Cys)-NH2 22.2 12.7 16.6 125 1.34 SEQ ID NO:20 Ac-Nle-c(Asp-His-D Nal- Arg-Trp-Ala-Lys)-NH2 1.17 1.56 0.277 3.24 4.22 SEQ ID NO:38 Ac-Nle-c(Asp-His-D Nal- Arg-Trp^-Ala-Lys)-NH2 0.648 2.78 0.329 1.4 1.97 SEQ ID NO:38 Ac-Nle-c(Cys-His-D Nal- Arg-Trp-Gaba-Cys)-NH2 0.393 1.86 0.375 1.11 1.05 SEQ ID NO:39 65

Compound Ki hMC1- R Ki hMC 3-R Ki hMC4- R Ki hMC 5-R Ki hMC1-R /MC4-R SEQ ID NO: Ac-Nle-c(Cys-His-D Nal- Arg-Trp-Ahx-Cys)-NH2 0.333 2.91 0.998 0.366 0.33 SEQ ID NO:39 Ac-hPhe-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)- NH2 0.461 2.45 0.931 1.37 0.50 SEQ ID NO:40 Ac-Cha-c(Asp-His-D N al-Arg-Trp-Gaba-Lys)-NH2 0.576 3.98 2.82 3.91 0.20 SEQ ID NO:40

Table 2C

Compound Ki hMC1- R Ki hMC 3-R Ki hMC4- R Ki hMC 5-R Ki hMC1-R /MC4-R SEQ ID NO: Ac-Arg-c(Cys-D-Ala-His-D- 2-Nal-Arg-Trp-Cys)-NH2 17.9 1.68 0.256 23.4 69.9 SEQ ID NO:49 cyclic AMP Bioassay

Intracellular cyclic AMP (cAMP) levels were determined by an electrochemiluminescence (ECL) assay (Meso Scale Discovery ®, Gaithersburg, MD; referred to hereinafter as MSD). CHO-K1 cells stably expressing the hMC receptor subtypes were suspended in RMPI 1640 ® assay buffer (RMPI 1640 buffer contains 0.5 mM isobutylmethylxanthine (IBMX), and 0.2% protein cocktail (MSD blocker A)). Transgenic CHO-K1 cells stably expressing hMC receptor subtypes 1, 3, 4 or 5 were dispensed at a density of approximately 7,000 cells/well in 384-well Multi-Array® plates (MSD) containing integrated carbon electrodes and coated with anti-cAMP antibody. Increasing concentrations of the test compounds were added and the cells were incubated for approximately 40 minutes at approximately 37°C. Following this incubation, lysis buffer (HEPES-buffered saline solution with MgCl2 and Triton X-100® at ph 7.3) containing 0.2% protein cocktail and 2.5 nM TAGTM ruthenium-labeled cAMP (MSD) was added and the cells were incubated for approximately 90 minutes at room temperature. At the end of the second incubation period read buffer (Tris-buffered solution containing an ECL co-reactant and Triton X-100 at ph 7.8) was added and the cAMP levels in the cell lysates were immediately determined 66 by ECL detection with a Sector Imager 6000 reader® (MSD). Data were analyzed using a computer-assisted non-linear regression analysis (XL fit; IDBS) and reported as either an EC50 value or a Kb value. EC50 represents the concentration of an agonist compound needed to obtain 50% of the maximum reaction response, e.g., 50% of the maximum level of cAMP as determined using the assay described above. The Kb value reflects the potency of an antagonist and is determined by Schild analysis. In brief, concentration-response curves of an agonist are carried out in the presence of increasing concentrations of an antagonist. The Kb value is the concentration of antagonist which would produce a 2-fold shift in the concentration-response curve for an agonist. It is calculated by extrapolating the line on a Schild plot to zero on the y-axis. A selection of compounds was tested using the above-discussed assays and the results are reported in Tables 3A, 3B, 3C, and 3D. TABLES 3A, 3B, 3C, and 3D - cAMP Bioassay Data for Selected Compounds

Table 3A

Compound EC50 hMC1- R EC50 hMC3- R EC50 hMC4- R EC50 hMC5- R EC50 hMC1-R /MC4-R SEQ ID NO: Ac-Arg-c(Cys-D- Ala-His-D-Phe- Arg-Trp-Cys)-NH2 5.79 5.25 0.313 1630 18.0 SEQ ID NO:50 Ac-D-Arg-c(Cys-D- Ala-His-D-Phe- Arg-Trp-Cys)-NH2 6.17 5.6 0.397 1020 16.0 SEQ ID NO:50 Ac-D-Arg-c(Cys-D- Ala-His-D-Phe- Arg-Trp-Pen)-NH2 26.5 10.5 0.493 2440 54.0 SEQ ID NO:51 Ac-D-Arg-c(Cys- His-D-Phe-Arg- Trp-Gaba-Pen)-NH2 8.43 32.4 0.959 2140 9.0 SEQ ID NO:52 Ac-Arg-c(Cys-His- D-Phe-Arg-Trp- Gaba-Pen)-NH2 4.23 8.09 0.719 23.2 6.0 SEQ ID NO:52 Ac-Arg-c(Cys-D- Ala-His-D-Phe- Arg-Trp-Pen)-NH2 48.3 13.3 0.79 10000 61.0 SEQ ID NO:51 67

Compound EC50 hMC1- R EC50 hMC3- R EC50 hMC4- R EC50 hMC5- R EC50 hMC1-R /MC4-R SEQ ID NO: Ac-D-Arg-c(Asp- His-D-Phe-Arg- Trp-Ala-Lys)-NH2 1.48 5.76 0.078 297 19.0 SEQ ID NO:53 Ac-Arg-c(Asp-His- D-Phe-Arg-Trp- Ala-Lys)-NH2 1.39 2.89 0.055 467 25.0 SEQ ID NO:53 ND = not determined

Table 3B

Compound EC50 hMC 1-R EC50 hMC 3-R EC50 hMC4- R EC50 hMC5- R EC50 hMC1-R /MC4-R SEQ ID NO: Ac-Nle-c(Cys-D-Ala-His- D-Phe-Arg-Trp-Cys)- NH2 2.4 0.33 0.078 420 31 SEQ ID NO:7 D-Phe-c(Cys-His-D- (Et)Tyr-Arg-Trp-p-Ala- D-Cys)-Thr-NH2 0.35 1.1 0.11 0.37 3 SEQ ID NO:24 Nle-c(Cys-His-D-Phe- Arg-Trp-Apn-Cys)-NH2 0.31 0.27 0.018 3.1 17 SEQ ID NO:27 Ac-Nle-c(Cys-His-D-Phe- Arg-Trp-Gaba-Pen)-NH2 0.28 0.24 0.028 3.9 10 SEQ ID NO:32 Nle-c(Cys-His-D-Phe- Arg-Trp-Gaba-Cys)-NH2 0.37 0.1 0.021 1.7 18 SEQ ID NO:34 Ac-Nle-c(Asp-His-D- Phe-Arg-Trp-p-Ala-Lys)- NH2 0.834 0.145 0.128 2.79 6.52 SEQ ID NO:1 Ac-Nle-c(Cys-His-D-Phe- Arg-Trp-Apn-Cys)-NH2 0.76 0.199 0.0492 1.73 15.45 SEQ ID NO:2 Ac-Cha-c(Asp-His-D- Phe-Arg-Trp-Gaba-Lys)- NH2 3.26 0.189 0.0949 30.2 34.35 SEQ ID NO:6 Ac-Nle-c(Asp-His-D- Phe-Arg-Trp-Gaba-Lys)- NH2 1.37 0.628 0.131 3.48 10.46 SEQ ID NO:6 Ac-hCha-c(Asp-His-D- Phe-Arg-Trp-Gaba-Lys)- NH2 2.27 3.32 7.24 415 0.31 SEQ ID NO:11 Ac-Nle-c(Pen-D-Ala-His- D-Phe-Arg-Trp-Cys)- NH2 ND 1.89 0.531 ND ND SEQ ID NO:21 68

Compound EC50 hMC 1-R EC50 hMC 3-R EC50 hMC4- R EC50 hMC5- R EC50 hMC1-R /MC4-R SEQ ID NO: Ac-Nle-c(Cys-D-Ala-His- D-Phe-Arg-Trp-Pen)- NH2 14.3 2.03 0.183 2240 78.14 SEQ ID NO:22 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-T rp-β -Ala-D-Cys)-Thr-NH2 0.345 2.71 5376 2.38 0.06 SEQ ID NO:24 D-Phe-c(Cys-His-D- (Et)Tyr-hArg-Bip^-Ala- D-Cys)-Thr-NH2 0.685 81.8 86.9 31.8 0.01 SEQ ID NO:26 Ac-Nle-c(Asp-D-Ala-His- D-Phe-Arg-Bal-Lys)-NH2 0.931 3.22 1.65 >10000 0.56 SEQ ID NO:28 Ac-Nle-c(Cys-D-Leu-His- D-Phe-Arg-Trp-Cys)- NH2 3.24 0.465 0.0915 78.5 35.41 SEQ ID NO:30 Ac-Nle-c(Cys-D-Cha- His-D-Phe-Arg-Trp-Cys)- NH2 0.819 0.541 0.453 45.3 1.81 SEQ ID NO:30 ND = not determined

Table 3C

Compound EC50 hMC1- R Kb hMC3- R Kb MC4- R EC50 hMC5- R SEQ ID NO: Ac-Nle-c(Cys-D-Ala-His- D Nal-Arg-Trp-Cys)- NH2 17.6 12.4 38.8 11.8 SEQ ID NO:16 Ac-Nle-c(Asp-His-D Nal-Arg-Trp-Ala-Lys)- NH2 0.619 2.98 0.109 0.189 SEQ ID NO:38 Ac-Nle-c(Asp-His-D N al-Arg-T φ-β-Ala-Lys)-NH2 0.913 0.536 0.346 0.489 SEQ ID NO:38 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Gaba-Cys)- NH2 0.231 18.4 0.782 0.153 SEQ ID NO:39 Ac-Nle-c(Cys-His-D Nal-Arg-Trp-Ahx-Cys)- NH2 0.581 10.8 0.967 0.126 SEQ ID NO:39 Ac-hPhe-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)- NH2 0.413 9.32 0.824 0.307 SEQ ID NO:40 69

Compound EC50 hMC1- R Kb hMC3- R Kb MC4- R EC50 hMC5- R SEQ ID NO: Ac-Cha-c(Asp-His-D Nal-Arg-Trp-Gaba-Lys)- NH2 1.27 3.02 0.442 0.736 SEQ ID NO:40 Ac-Nle-c(Cys-D-Ala- His-D Nal-Arg Nal- Cys)-NH2 383 61.5 53.6 2842 SEQ ID NO:16

Table 3D

Compound EC50 hMC1- R Kb hMC3- R Kb MC4- R EC50 hMC5- R SEQ ID NO: Ac-Arg-c(Cys-D-Ala- His-D Nal-Arg-Trp- Cys)-NH2 193 5.72 1.58 1111 SEQ ID NO:49

Example 4: In vivo studies

Compounds of the present invention can be and were tested for an effect upon food intake and/or body weight according to the following procedures. One skilled in the art would know that procedures similar to those described herein may be used to assay the effect of the compounds of the invention upon food intake and/or body weight.

Ligand compounds activating melanocortin receptors tested in the in vivo studies were as follows (Table 4): Table 4

Ligand Code Structure Compound A Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:7 Compound B Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:22 Compound C Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO:32 Compound D D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-p-Ala-D-Cys)-Thr-NH2 SEQ ID NO:24 Compound E Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:50 Compound F Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:50 Compound G Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:51 70

Acute feeding experiments (fasting)

Male Sprague Dawley rats (250g) were housed in individual cages and maintained under 12:12 hour light:dark conditions. The rats were fasted for 18 hours prior to the start of the experiment with water available ad libitum. At time 0, the rats were injected subcutaneously (sc) with selected compounds at doses of either 500 or 100 nmole/kg, or with vehicle, and were provided with food. Individual food consumption was measured at about 1, 2, 3, 4, 5 and 6 hours after injection. Data for selected compounds of the invention are reported in Figures 1A and 1B.

Acute feeding experiments (non fasting)

Male Sprague Dawley rats (250g) are housed in individual cages and maintained under 12:12 hour light:dark conditions. Food and water is available ad libitum throughout the experiment. At time 0, the rats are injected sc with compound at doses of either 500 or 100 nmole/kg, or with vehicle. Individual food consumption is measured at about 1, 2, 3, 4, 5 and 6 hours after injection.

Chronic feeding experiments

Male Sprague Dawley rats (250g) were housed in individual cages and maintained under 12:12 hour light:dark conditions with both food and water available ad libitum. The rats were injected sc 3x/day (approximately 0800 hour, 1200 hour, and 1600 hour) with compound at various doses or with vehicle for 7 days. Individual body weight and food consumption were measured daily. Data for selected compounds of the invention are reported in Figures 2A and 2B, Figures 3A and 3B, and Figures 4A and 4B.

Administration and Use

The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g., 71 tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of polylactic-glycolic acids). A typical method of making a salt of a peptide of the present invention is well known in the art and can be accomplished by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt results from the purification of the peptide by using preparative HPLC, eluting with TFA containing buffer solutions) can be converted into another salt, such as an acetate salt, by dissolving the peptide in a small amount of 0.25 N acetic acid aqueous solution. The resulting solution is applied to a semiprep HPLC column (Zorbax®, 300 SB, C-8). The column is eluted with: (1) 0.1N ammonium acetate aqueous solution for 0.5 hours; (2) 0.25N acetic acid aqueous solution for 0.5 hours; and (3) a linear gradient (20% to 100% of solution B over 30 minutes) at a flow rate of 4 ml/min (solution A is 0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid in acetonitrile/water, 80:20). The fractions containing the peptide are collected and lyophilized to dryness.

As is well known to those skilled in the art, the known and potential uses of peptides with melanocortin receptor (MC-R) agonist or antagonist activity is varied and multitudinous, thus the administration of the compounds of this invention for purposes of eliciting an agonist effect can have the same effects and uses as melanocortin itself.

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula (I) in association with a pharmaceutically acceptable carrier.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. In general, an effective dosage for the activities of this invention is in the range of 1x10-7 to 200 mg/kg/day, preferably 1x10-4 to 100 mg/kg/day which can be administered as a single dose or divided into multiple doses.

The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or 72 implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles 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 adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Preparations may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. Preparations can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax. 73

Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.

Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications. U.S. Patent No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Patent No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form. U.S. Patent No. 5,821,221 teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. Patent No. 5,916,883 teaches sustained release compositions comprising a bioactive agent and cyclodextrin.

99 members in 21 offices

This recordMember, by publication datePriority claim11 more offices are in the list below

Priority claims12

Priority claims
Document	Office	Kind	Date
69777905	United States of America	P	2005-07-08
69777905	United States of America	P	2005-07-08
74885005	United States of America	P	2005-12-09
74885005	United States of America	P	2005-12-09
2006026586	United States of America	W	2006-07-10
2006026586	United States of America	W	2006-07-10
60697779	–	–	–
60748850	–	–	–
PCTUS2006026586	–	–	–
US20050697779P	–	–	–
US20050748850P	–	–	–
WO2006US26586	–	–	–

Members99

Family members, oldest first
Document	Office	Kind
AU2006269261A1	Australia	A1	2007-01-18
CA2614615A1	Canada	A1	2007-01-18
CA2793119A1	Canada	A1	2007-01-18
CA3044795A1	Canada	A1	2007-01-18
CA3228910A1	Canada	A1	2007-01-18
WO2007008704A2	World Intellectual Property Organization (WIPO)	A2	2007-01-18
WO2007008704A3	World Intellectual Property Organization (WIPO)	A3	2007-10-11
IL188545A0	Israel	A0	2008-04-13
IL188545D0	Israel	D0	2008-04-13
EP1915167A2	European Patent Office (EPO)	A2	2008-04-30
KR20080049711A	Republic of Korea	A	2008-06-04
CN101257916A	China	A	2008-09-03
JP2009500427A	Japan	A	2009-01-08
RU2008104803A	Russian Federation	A	2009-08-20
AU2009230799A1	Australia	A1	2009-11-19
AU2006269261B2	Australia	B2	2009-12-17
RU2380372C2	Russian Federation	C2	2010-01-27
KR20100016120A	Republic of Korea	A	2010-02-12
CN101676298A	China	A	2010-03-24
NZ565217A	New Zealand	A	2010-03-26
EP1915167A4	European Patent Office (EPO)	A4	2010-04-07
JP2010090130A	Japan	A	2010-04-22
IL201732A0	Israel	A0	2010-06-16
IL201732D0	Israel	D0	2010-06-16
SG163585A1	Singapore	A1	2010-08-30
EP2236151A1	European Patent Office (EPO)	A1	2010-10-06
US2010279922A1	United States of America	A1	2010-11-04
KR100997177B1	Republic of Korea	B1	2010-11-29
RU2009131092A	Russian Federation	A	2011-02-20
EP2286825A2	European Patent Office (EPO)	A2	2011-02-23
EP2286825A3	European Patent Office (EPO)	A3	2011-07-27
JP4734411B2	Japan	B2	2011-07-27
US2011183886A1	United States of America	A1	2011-07-28
IL188545A	Israel	A	2011-08-31
HK1149190A	Hong Kong, China	A	2011-09-30
HK1149190A1	Hong Kong, China	A1	2011-09-30
US8039435B2	United States of America	B2	2011-10-18
RU2439079C2	Russian Federation	C2	2012-01-10
AU2009230799B2	Australia	B2	2012-02-09
EP2236151B1	European Patent Office (EPO)	B1	2012-05-23
PT2236151E	Portugal	E	2012-07-02
DK2236151T3	Denmark	T3	2012-07-09
NZ580806A	New Zealand	A	2012-07-27
ES2386862T3	Spain	T3	2012-09-03
CA2614615C	Canada	C	2012-10-16
PL2236151T3	Poland	T3	2012-10-31
EP2548568A2	European Patent Office (EPO)	A2	2013-01-23
KR101232201B1	Republic of Korea	B1	2013-02-12
CN101257916B	China	B	2013-04-03
EP2548568A3	European Patent Office (EPO)	A3	2013-07-17
JP2013253090A	Japan	A	2013-12-19
CN103755786A	China	A	2014-04-30
JP2015232003A	Japan	A	2015-12-24
JP5889513B2	Japan	B2	2016-03-22
CN103755786B	China	B	2016-05-11
IL201732AThis record	Israel	A	2016-07-31
JP5965520B2	Japan	B2	2016-08-03
CN105837661A	China	A	2016-08-10
EP2286825B1	European Patent Office (EPO)	B1	2016-09-28
US9458195B2	United States of America	B2	2016-10-04
US2016368962A1	United States of America	A1	2016-12-22
PT2286825T	Portugal	T	2017-01-02
DK2286825T3	Denmark	T3	2017-01-09
ES2604328T3	Spain	T3	2017-03-06
PL2286825T3	Poland	T3	2017-06-30
HUE031731T2	Hungary	T2	2017-07-28
IL246392A	Israel	A	2017-07-31
US2017240595A1	United States of America	A1	2017-08-24
US9850280B2	United States of America	B2	2017-12-26
EP2548568B1	European Patent Office (EPO)	B1	2018-01-10
DK2548568T3	Denmark	T3	2018-03-12
PT2548568T	Portugal	T	2018-03-21
ES2663916T3	Spain	T3	2018-04-17
US2018105557A1	United States of America	A1	2018-04-19
PL2548568T3	Poland	T3	2018-06-29
EP3354273A1	European Patent Office (EPO)	A1	2018-08-01
HUE037147T2	Hungary	T2	2018-08-28
US2018305406A1	United States of America	A1	2018-10-25
CA2793119C	Canada	C	2019-07-23
HK1258965A	Hong Kong, China	A	2019-11-22
HK1258965A1	Hong Kong, China	A1	2019-11-22
US2020095281A1	United States of America	A1	2020-03-26
EP3354273B1	European Patent Office (EPO)	B1	2021-03-24
DK3354273T3	Denmark	T3	2021-06-28
PT3354273T	Portugal	T	2021-06-28
PL3354273T3	Poland	T3	2021-10-11
SI3354273T1	Slovenia	T1	2021-10-29
ES2877349T3	Spain	T3	2021-11-16
HUE055154T2	Hungary	T2	2021-11-29
NL301150I1	Netherlands (Kingdom of the)	I1	2021-12-08
EP3925614A2	European Patent Office (EPO)	A2	2021-12-22
HUS2100054I1	Hungary	I1	2021-12-28
FR21C1060I1	France	I1	2022-01-21
EP3925614A3	European Patent Office (EPO)	A3	2022-03-23
US2022127305A1	United States of America	A1	2022-04-28
NL301150I2	Netherlands (Kingdom of the)	I2	2022-11-24
FR21C1060I2	France	I2	2022-12-02
CN105837661B	China	B	2024-10-15
CN119119190A	China	A	2024-12-13

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	Event	Code
2020-07-30	Patent renewedKB	KB
2016-12-29	Patent renewedKB	KB
2016-11-30	Patent grantedGrantedFF	FF

Melanocortin receptor ligands

Abstract

Term

MELANOCORTIN RECEPTOR LIGANDS

BACKGROUND OF THE INVENTION

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION OF THE INVENTION 36

CH2

R', R

-—N

O

N

I

HO

N

I

EXAMPLES

Priority claims12

Members99

Over the term

Events

Numbers

Titles2

Classification