Melanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [5]) are activated by members of the melanocortin family (α-MSH (POMC, P01189), β-MSH (POMC, P01189) and γ-MSH (POMC, P01189) forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH (POMC, P01189)). Endogenous antagonists include agouti (ASIP, P42127) and agouti-related protein (AGRP, O00253). ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test. Setmelanotide was approved by the US FDA for weight management in patients with POMC, PCSK1 or LEPR defiency, bremelanotide was approved by the US FDA for generalized hypoactive sexual desire disorder in premenopausal women, and NDP-MSH (afamelanotide) was approved by the EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development.

Polymorphisms of the MC₁ receptor have been linked to variations in skin pigmentation. Defects of the MC₂ receptor underlie familial glucocorticoid deficiency. Polymorphisms of the MC₄ receptor have been linked to obesity [2,4].

* Key recommended reading is highlighted with an asterisk

* Caruso V, Lagerström MC, Olszewski PK, Fredriksson R, Schiöth HB. (2014) Synaptic changes induced by melanocortin signalling. Nat Rev Neurosci, 15 (2): 98-110. [PMID:24588018]

Farooqi IS, O'Rahilly S. (2008) Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity. Nat Clin Pract Endocrinol Metab, 4 (10): 569-77. [PMID:18779842]

* Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

* Renquist BJ, Lippert RN, Sebag JA, Ellacott KL, Cone RD. (2011) Physiological roles of the melanocortin MC₃ receptor. Eur J Pharmacol, 660 (1): 13-20. [PMID:21211527]

1. Bednarek MA, MacNeil T, Kalyani RN, Tang R, Van der Ploeg LH, Weinberg DH. (2001) Selective, high affinity peptide antagonists of alpha-melanotropin action at human melanocortin receptor 4: their synthesis and biological evaluation in vitro. J Med Chem, 44 (22): 3665-72. [PMID:11606131]

2. Chagnon YC, Chen WJ, Pérusse L, Chagnon M, Nadeau A, Wilkison WO, Bouchard C. (1997) Linkage and association studies between the melanocortin receptors 4 and 5 genes and obesity-related phenotypes in the Québec Family Study. Mol Med, 3 (10): 663-73. [PMID:9392003]

3. Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G et al.. (2020) Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol, 8 (12): 960-970. [PMID:33137293]

4. Farooqi IS, O'Rahilly S. (2008) Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity. Nat Clin Pract Endocrinol Metab, 4 (10): 569-77. [PMID:18779842]

5. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

6. Grieco P, Balse PM, Weinberg D, MacNeil T, Hruby VJ. (2000) D-Amino acid scan of gamma-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity. J Med Chem, 43 (26): 4998-5002. [PMID:11150170]

7. Grieco P, Cai M, Han G, Trivedi D, Campiglia P, Novellino E, Hruby VJ. (2007) Further structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5. Peptides, 28 (6): 1191-6. [PMID:17482720]

8. Kopanchuk S, Veiksina S, Petrovska R, Mutule I, Szardenings M, Rinken A, Wikberg JE. (2005) Co-operative regulation of ligand binding to melanocortin receptor subtypes: evidence for interacting binding sites. Eur J Pharmacol, 512 (2-3): 85-95. [PMID:15840392]

9. Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, Culler MD, Yang H, Dixit VD, Butler AA. (2009) Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides, 30 (10): 1892-900. [PMID:19646498]

10. Nickolls SA, Cismowski MI, Wang X, Wolff M, Conlon PJ, Maki RA. (2003) Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity. J Pharmacol Exp Ther, 304 (3): 1217-27. [PMID:12604699]

11. Schioth HB, Muceniece R, Wikberg JE, Chhajlani V. (1995) Characterisation of melanocortin receptor subtypes by radioligand binding analysis. Eur J Pharmacol, 288 (3): 311-317. [PMID:7774675]

12. Schiöth HB, Mutulis F, Muceniece R, Prusis P, Wikberg JE. (1998) Discovery of novel melanocortin4 receptor selective MSH analogues. Br J Pharmacol, 124 (1): 75-82. [PMID:9630346]

13. Sebhat IK, Martin WJ, Ye Z, Barakat K, Mosley RT, Johnston DB, Bakshi R, Palucki B, Weinberg DH, MacNeil T, Kalyani RN, Tang R, Stearns RA, Miller RR, Tamvakopoulos C, Strack AM, McGowan E, Cashen DE, Drisko JE, Hom GJ, Howard AD, MacIntyre DE, van der Ploeg LH, Patchett AA, Nargund RP. (2002) Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist. J Med Chem , 45: 4589-4593. [PMID:12361385]

Subcommittee members: Tung M. Fong (Chairperson) Clinical Development Vyluma Inc Bridgewater, NJ USA Helgi Schiöth (Chairperson) Dept. of Neuroscience Biomedical Centre Uppsala University Uppsala Sweden Ira Gantz (Past chairperson) Merck & Co. Inc. RY34-A202 P.O. Box 2000 Rahway NJ 07065-0900 USA Vanni Caruso University of Tasmania (UTAS) Faculty of Pharmacy 7001 Hobart Tasmania Australia Roger D. Cone University of Michigan 210 Washtenaw Avenue Ann Arbor MI, 48109-2216 USA Sadaf Farooqi University of Cambridge Metabolic Research Laboratories Institute of Metabolic Science Addenbrooke's Hospital Cambridge UK Carrie Haskell-Luevano University of Minnesota College of Pharmacy Department of Medicinal Chemistry 8-101 Weaver-Densford Hall 308 Harvard St. SE Minneaplois MN, 55455 USA Victor J. Hruby Department of Chemistry University of Arizona Tucson AZ 85721-0002 USA Kathleen G. Mountjoy Department of Paediatrics Research Centre for Development of Medicine University of Auckland School of Medicine Park Road Auckland New Zealand Jarl E. S. Wikberg Department of Pharmaceutical Pharmacology Uppsala University Uppsala Sweden

Other contributors: Biao-Xin Chai Department of Surgery University of Michigan Medical Center Ann Arbor MI USA Adrian J. L. Clark Department of Chemical Endocrinology Molecular Endocrinology St. Bartholomew's Hospital 33 Queen's Road London EC1A 7BE UK Alex N. Eberle Department of Research Universitsspital Hebelstrasse 20 Basel CH-4031 Switzerland Colin Pouton School of Pharmacy and Pharmacology University of Bath Claverton Down Bath BA2 7AY UK Jeffrey B. Tatro Endocrine Division New England Medical Center Hospital Box 268 750 Washington Street Boston MA 02111-1533 USA