Melanocortin receptor: Wikis


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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[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,[6] and activated by synthetic (ie: 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]



MC2 selective
MC3 selective
  • gamma-MSH
MC4 selective

Antagonists and inverse agonists

MC1 selective
MC4 selective
  • Agouti-related peptide (inverse agonist at both MC3 and MC4)
  • HS-014
  • HS-024
  • MCL-0042[18]
  • MCL-0129[19]
  • MPB-10
  • SHU-9119 (agonist at MC1 and MC5, antagonist at MC3 and MC4)


  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. 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: 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. 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. 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. 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: 359–65. 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. 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. 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.  

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