Melanocortin receptor

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

Contents

There are five known members of the melanocortin receptor system [1] each with differing specificities for melanocortins: [2] [3] [4]

These receptors are inhibited by endogenous inverse agonists agouti signalling peptide and agouti-related peptide, [7] and activated by synthetic (i.e. afamelanotide) and endogenous agonist melanocyte-stimulating hormones. [8]

Selective ligands

Several selective ligands for the melanocortin receptors are known, [9] [10] [11] [12] and some synthetic compounds have been investigated as potential tanning, anti-obesity and aphrodisiac drugs, with tanning effects mainly from stimulation of MC1, [13] while anorectic and aphrodisiac effects appear to involve both MC3 and MC4. [14] MC1, MC3 and MC4 are widely expressed in the brain, and are also thought to be responsible for effects on mood and cognition. [15] [16] [17] [18]

Agonists

Non-selective
MC1-selective
MC4-selective
Unknown (but for certain MC2-acting)

Antagonists and inverse agonists

Non-selective
MC2-selective
MC4-selective

Unknown

References

  1. ↑ "Melanocortins and the Melanocortin Receptor". Archived from the original on 2007-04-11. Retrieved 2007-03-14.
  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. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  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.
  10. ↑ 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.
  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-[(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.
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