Biology:Melanocortin receptor

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Short description: G protein-coupled 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 is associated with childhood growth, accrual of lean mass and onset of puberty.[5]
  • MC4R. Defects in MC4R are a cause of autosomal dominant obesity, accounting for 6% of all cases of early-onset obesity.[6]
  • MC5R. MC5R

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
  • BMS-470,539
MC4-selective
Unknown (but for certain MC2-acting)

Antagonists and inverse agonists

Non-selective
MC4-selective
  • HS-014
  • HS-024
  • MCL-0042[19]
  • MCL-0129[20]
  • MPB-10
  • SHU-9119 (agonist at MC1 and MC5, antagonist at MC3 and MC4)

Unknown

References

  1. ↑ "Melanocortins and the Melanocortin Receptor". http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/bodyweight/melanocortins.html. 
  2. ↑ "Melanocortins and their receptors and antagonists". Current Drug Targets 4 (7): 586–97. October 2003. doi:10.2174/1389450033490858. PMID 14535656. 
  3. ↑ "Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization". Peptides 27 (4): 921–30. April 2006. 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. ↑ "Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene". N. Engl. J. Med. 348 (12): 1085–95. 2003. doi:10.1056/NEJMoa022050. PMID 12646665. 
  7. ↑ "Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors". Biochemistry 44 (9): 3418–31. 2005. doi:10.1021/bi0478704. PMID 15736952. 
  8. ↑ "Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists". Biochemistry 44 (34): 11329–41. 2005. doi:10.1021/bi0501840. PMID 16114870. 
  9. ↑ "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. November 2003. doi:10.1021/jm030119t. PMID 14584947. 
  10. ↑ "Overview of endogenous and synthetic melanocortin peptides". Cellular and Molecular Biology (Noisy-le-Grand, France) 52 (2): 3–20. 2006. PMID 16914082. 
  11. ↑ "Design, synthesis and biological evaluation of ligands selective for the melanocortin-3 receptor". Current Topics in Medicinal Chemistry 7 (11): 1107–19. 2007. doi:10.2174/156802607780906645. PMID 17584128. 
  12. ↑ "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. January 2008. doi:10.1021/jm070461w. PMID 18088090. 
  13. ↑ "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. June 2003. doi:10.1111/j.1749-6632.2003.tb03200.x. PMID 12851336. 
  14. ↑ "Melanocortin receptors, melanotropic peptides and penile erection". Current Topics in Medicinal Chemistry 7 (11): 1098–1106. 2007. doi:10.2174/1568026610707011111. PMID 17584130. 
  15. ↑ "Anxiety-like behavior induced by IL-1beta is modulated by alpha-MSH through central melanocortin-4 receptors". Peptides 27 (6): 1451–6. June 2006. 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. ↑ "Role of alpha-melanocyte stimulating hormone and melanocortin 4 receptor in brain inflammation". Peptides 29 (10): 1825–35. October 2008. doi:10.1016/j.peptides.2008.06.009. PMID 18625277. 
  18. ↑ "Memory impairment induced by IL-1beta is reversed by alpha-MSH through central melanocortin-4 receptors". Brain, Behavior, and Immunity 23 (6): 817–22. March 2009. doi:10.1016/j.bbi.2009.03.001. PMID 19275930. 
  19. ↑ "MCL0042: a nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity". Pharmacology Biochemistry and Behavior 82 (4): 621–6. December 2005. doi:10.1016/j.pbb.2005.11.001. PMID 16337261. 
  20. ↑ "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. February 2003. doi:10.1124/jpet.102.044826. PMID 12538838. 

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