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Melanocortin receptors are members of the rhodopsin family of 7-transmembrane G protein-coupled receptors.

There are five known members of the melanocortin receptor system each with differing specificities for melanocortins:

• MC1R. MC1R is associated with pigmentation genetics.
• MC2R. MC2R is also known as the ACTH receptor or corticotropin receptor because it is specific for ACTH alone.
• MC3R. MC3R is associated with childhood growth, accrual of lean mass and onset of puberty.
• MC4R. Defects in MC4R are a cause of autosomal dominant obesity, accounting for 6% of all cases of early-onset obesity.
• MC5R. MC5R

These receptors are inhibited by endogenous inverse agonists agouti signalling peptide and agouti-related peptide, and activated by synthetic (i.e. afamelanotide) and endogenous agonist melanocyte-stimulating hormones.

Selective ligands

Several selective ligands for the melanocortin receptors are known, and some synthetic compounds have been investigated as potential tanning, anti-obesity and aphrodisiac drugs, with tanning effects mainly from stimulation of MC₁, while anorectic and aphrodisiac effects appear to involve both MC₃ and MC₄. MC₁, MC₃ and MC₄ are widely expressed in the brain, and are also thought to be responsible for effects on mood and cognition.

Agonists

Non-selective

• α-MSH
• β-MSH
• γ-MSH
• Afamelanotide
• Bremelanotide
• Melanotan II
• Modimelanotide
• Setmelanotide

MC₁-selective

• BMS-470,539

MC₄-selective

• PF-00446687
• PL-6983
• THIQ

Unknown (but for certain MC₂-acting)

• Alsactide
• Tetracosactide

Antagonists and inverse agonists

Non-selective

• Agouti-related peptide
• Agouti signalling peptide

MC₂-selective

• Atumelnant (CRN04894)

MC₄-selective

• HS-014
• HS-024
• MCL-0042
• MCL-0129
• MPB-10
• SHU-9119 (agonist at MC₁ and MC₅, antagonist at MC₃ and MC₄)

Unknown

• Semax

References

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4. Dores RM (April 2009). "Adrenocorticotropic hormone, melanocyte-stimulating hormone, and the melanocortin receptors: revisiting the work of Robert Schwyzer: a thirty-year retrospective". Annals of the New York Academy of Sciences. 1163 (1): 93–100. doi:10.1111/j.1749-6632.2009.04434.x. PMID 19456331.
5. Lam, B.Y.H., Williamson, A., Finer, S. et al. MC3R links nutritional state to childhood growth and the timing of puberty. Nature (2021). doi:10.1038/s41586-021-04088-9
6. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S (2003). "Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene". N. Engl. J. Med. 348 (12): 1085–95. doi:10.1056/NEJMoa022050. PMID 12646665.
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9. Balse-Srinivasan P, Grieco P, Cai M, Trivedi D, Hruby VJ (November 2003). "Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. Discovery of highly selective hMC3R, hMC4R, and hMC5R analogues". Journal of Medicinal Chemistry. 46 (23): 4965–73. doi:10.1021/jm030119t. PMID 14584947.
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11. Hruby VJ, Cai M, Cain JP, Mayorov AV, Dedek MM, Trivedi D (2007). "Design, synthesis and biological evaluation of ligands selective for the melanocortin-3 receptor". Current Topics in Medicinal Chemistry. 7 (11): 1107–19. doi:10.2174/156802607780906645. PMC 2274922. PMID 17584128.
12. Mayorov AV, Cai M, Palmer ES, Dedek MM, Cain JP, Van Scoy AR, Tan B, Vagner J, Trivedi D, Hruby VJ (January 2008). "Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor". Journal of Medicinal Chemistry. 51 (2): 187–95. doi:10.1021/jm070461w. PMC 2587288. PMID 18088090.
13. Kadekaro AL, Kanto H, Kavanagh R, Abdel-Malek ZA (June 2003). "Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival". Annals of the New York Academy of Sciences. 994 (1): 359–65. doi:10.1111/j.1749-6632.2003.tb03200.x. PMID 12851336.
14. King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H (2007). "Melanocortin receptors, melanotropic peptides and penile erection". Current Topics in Medicinal Chemistry. 7 (11): 1098–1106. doi:10.2174/1568026610707011111. PMC 2694735. PMID 17584130.
15. Cragnolini AB, Schiöth HB, Scimonelli TN (June 2006). "Anxiety-like behavior induced by IL-1beta is modulated by alpha-MSH through central melanocortin-4 receptors". Peptides. 27 (6): 1451–6. doi:10.1016/j.peptides.2005.10.020. PMID 16325304.
16. Catania A (July 2008). "Neuroprotective actions of melanocortins: a therapeutic opportunity". Trends in Neurosciences. 31 (7): 353–60. doi:10.1016/j.tins.2008.04.002. PMID 18550183.
17. Lasaga M, Debeljuk L, Durand D, Scimonelli TN, Caruso C (October 2008). "Role of alpha-melanocyte stimulating hormone and melanocortin 4 receptor in brain inflammation". Peptides. 29 (10): 1825–35. doi:10.1016/j.peptides.2008.06.009. hdl:11336/104816. PMID 18625277.
18. Gonzalez PV, Schiöth HB, Lasaga M, Scimonelli TN (March 2009). "Memory impairment induced by IL-1beta is reversed by alpha-MSH through central melanocortin-4 receptors". Brain, Behavior, and Immunity. 23 (6): 817–22. doi:10.1016/j.bbi.2009.03.001. hdl:11336/104814. PMID 19275930.
19. Chaki S, Oshida Y, Ogawa S, Funakoshi T, Shimazaki T, Okubo T, Nakazato A, Okuyama S (December 2005). "MCL0042: a nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity". Pharmacology Biochemistry and Behavior. 82 (4): 621–6. doi:10.1016/j.pbb.2005.11.001. PMID 16337261.
20. Chaki S, Hirota S, Funakoshi T, Suzuki Y, Suetake S, Okubo T, Ishii T, Nakazato A, Okuyama S (February 2003). "Anxiolytic-like and antidepressant-like activities of MCL0129 (1--4-piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor". The Journal of Pharmacology and Experimental Therapeutics. 304 (2): 818–26. doi:10.1124/jpet.102.044826. PMID 12538838.

External links

• "Melanocortin Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Melanocortin+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Calculated spatial position of melanocortin-4 receptor in the lipid bilayer, inactive state with antagonist and active state with agonist

• G protein-coupled receptors