Melanocortin receptor

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^[1] each with differing specificities for melanocortins:^[2][3][4]

• 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
• MC4R. Defects in MC4R are a cause of autosomal dominant obesity, accounting for 6% of all cases of early-onset obesity.^[5]
• MC5R. MC5R

These receptors are inhibited by endogenous inverse agonists agouti signalling peptide and agouti-related peptide,^[6] and activated by synthetic (i.e. afamelanotide) and endogenous agonist melanocyte-stimulating hormones.^[7]

Selective ligands

Several selective ligands for the melanocortin receptors are known,^{[8][9][10][11]} and some synthetic compounds have been investigated as potential tanning, anti-obesity and aphrodisiac drugs, with tanning effects mainly from stimulation of MC₁,^[12] while anorectic and aphrodisiac effects appear to involve both MC₃ and MC₄.^[13] MC₁, MC₃ and MC₄ are widely expressed in the brain, and are also thought to be responsible for effects on mood and cognition.^{[14][15][16][17]}

Agonists

Non-selective

• α-MSH
• β-MSH
• γ-MSH
• ACTH
• 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

MC₄-selective

• HS-014
• HS-024
• MCL-0042^[18]
• MCL-0129^[19]
• MPB-10
• SHU-9119 (agonist at MC₁ and MC₅, antagonist at MC₃ and MC₄)

Unknown

• Semax

References

1. Melanocortins and the Melanocortin Receptor
2. Voisey J, Carroll L, van Daal A (October 2003). "Melanocortins and their receptors and antagonists". Current Drug Targets 4 (7): 586–97. doi:10.2174/1389450033490858. PMID 14535656.
3. Hadley ME, Dorr RT (April 2006). "Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization". Peptides 27 (4): 921–30. doi:10.1016/j.peptides.2005.01.029. PMID 16412534.
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. 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.
6. Chai B, Pogozheva I, Lai Y, Li J, Neubig R, Mosberg H, Gantz I (2005). "Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors". Biochemistry 44 (9): 3418–31. doi:10.1021/bi0478704. PMID 15736952.
7. Pogozheva I, Chai B, Lomize A, Fong T, Weinberg D, Nargund R, Mulholland M, Gantz I, Mosberg H (2005). "Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists". Biochemistry 44 (34): 11329–41. doi:10.1021/bi0501840. PMC 2532597. PMID 16114870.
8. 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.
9. Wilson KR, Todorovic A, Proneth B, Haskell-Luevano C (2006). "Overview of endogenous and synthetic melanocortin peptides". Cellular and Molecular Biology (Noisy-le-Grand, France) 52 (2): 3–20. PMID 16914082.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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. PMID 18625277.
17. 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. PMID 19275930.
18. 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.
19. 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-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]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 US 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