melanocortin

The five melanocortin receptors are seven-transmembrane G-protein coupled receptors with differing ligand affinities, tissue and cell type expression, and downstream functions.Butler, A.A., et al., A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling. Front Neurosci, 2017. 11: p. 128. MC1R is expressed on melanocytes, macrophages, epithelial cells, endothelial cells, fibroblasts, monocytes and numerous other immune cells, but is also present in brain, testis, and intestine.Salazar-Onfray, F., et al., Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker. Br J Cancer, 2002. 87(4): p. 414-22. Its main functions are in melanogenesis and anti-inflammatory signaling.Wolf Horrell, E.M., M.C. Boulanger, and J.A. D'Orazio, Melanocortin 1 Receptor: Structure, Function, and Regulation. Front Genet, 2016. 7: p. 95. MC2R is expressed in the adrenal cortex and adipocytes and promotes steroidogenesis.Fridmanis, D., A. Roga, and J. Klovins, ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms? Front Endocrinol (Lausanne), 2017. 8: p. 13. MC3R and MC4R are primarily expressed in the brain and regulate energy homeostasis. MC3R is additionally involved in immunomodulation while MC4R has a role in sexual function.Catania, A., et al., Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev, 2004. 56(1): p. 1-29.Martin, W.J. and D.E. MacIntyre, Melanocortin receptors and erectile function. Eur Urol, 2004. 45(6): p. 706-13. MC5R is highly expressed in skin and adrenal glands and has a role in exocrine function.Hatta, N., et al., Expression, candidate gene, and population studies of the melanocortin 5 receptor. J Invest Dermatol, 2001. 116(4): p. 564-70. MC2R is activated exclusively by ACTH, whereas the other 4 receptors can be activated by ACTH, α-MSH, β-MSH, and γ-MSH, although the binding affinities differ. For all the melanocortin receptors, binding of an agonistic ligand activates the receptor, leading to dissociation of the G protein and activation of the enzyme adenyl cyclase. Adenyl cyclase then cleaves ATP to generate the second messenger cyclic AMP (cAMP), which in turn activates multiple downstream pathways.  

There are two known accessory proteins belonging to the melanocortin system which modulate function of the receptors. These are melanocortin-2-receptor accessory protein (MRAP) and MRAP2.Chan, L.F., et al., MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc Natl Acad Sci U S A, 2009. 106(15): p. 6146-51.

In 2019, the FDA approved the first drug targeting melanocortin receptors, Vyleesi (Bremelanotide) which was developed by Palatin Technologies, Inc.  The Melanocortin system has been largely unexplored in drug development but recent approvals, its novelty and wide-spread application across indications has led it to the frontier of new discoveries in medicine. Since Vyleesi approval  multiple companies have initiated drug discovery programs targeting the melanocortin system. Bremelanotide (Vyleesi) is approved for treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.Administration, U.F.a.D. FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women. 2019; Available from: [https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women#:~:text=FDA%20approves%20new%20treatment%20for%20hypoactive%20sexual%20desire%20disorder%20in%20premenopausal%20women,-Share&text=The%20U.S.%20Food%20and%20Drug,(HSDD)%20in%20premenopausal%20women]{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}. At therapeutic dose levels, it activates MC1R and MC4R.Administration, U.F.a.D. Vyleesi prescribing information. 2019; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210557s000lbl.pdf.

Setmelanotide (Imcivree) is an MC4R agonist approved for chronic weight management in patients with genetic obesity.Administration, U.F.a.D. FDA approves first treatment for weight management for people with certain rare genetic conditions. 2020; Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions#:~:text=%5B11%2F27%2F2020%5D,POMC)%20deficiency%2C%20proprotein%20subtilisin%2F.Markham, A., Setmelanotide: First Approval. Drugs, 2021. 81(3): p. 397-403.

Afamelanotide (Scenesse) is an MC1R agonist approved for patients with erythropoietic protoporphyria to increase pain-free light exposure.Administration, U.F.a.D. FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder. 2019; Available from: [https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-increase-pain-free-light-exposure-patients-rare-disorder]{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}.

PL9643, an ophthalmic solution, is being tested in phase 3 clinical trials to determine safety and efficacy in patients with dry eye.Administration, U.F.a.D. A Phase 3, Multi-Center Study Evaluating PL9643 in Patients With Dry Eye (MELODY-1). 2022; Available from: https://clinicaltrials.gov/ct2/show/NCT05201170?term=palatin&draw=2&rank=1. PL9643 activates MC1R, MC3R, MC4R and MC5R. Completed Phase 2 studies demonstrated positive results for the treatment of dry eye disease.Administration, U.F.a.D. Efficacy and Safety of PL9643 Ophthalmic Solution in Subjects With Dry Eye. 2020; Available from: https://clinicaltrials.gov/ct2/show/NCT04268069?term=palatin&draw=2&rank=9.

Dersimelagon (MT-7117) is an orally administered MC1R agonist being tested in phase 3 clinical trials to evaluate safety and tolerability in patients with erythropoietic protoporphyria or X-linked protoporphyria.Administration, U.F.a.D. Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP). 2021; Available from: https://clinicaltrials.gov/ct2/show/NCT05005975?term=mt-7117&draw=2&rank=9.

Resomelagon (AP1189) is an orally administered MC1R and MC3R agonist being tested in three phase 2 clinical trials to study safety and efficacy in patients with rheumatoid arthritis and idiopathic membranous nephropathy.Administration, U.F.a.D. A Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Treatment With AP1189 in Patients With iMN. 2020; Available from: https://clinicaltrials.gov/ct2/show/NCT04456816?term=ap1189&draw=2&rank=2.Administration, U.F.a.D. A Safety & Efficacy Study of Treatment With AP1189 in Rheumatoid Arthritis Patients naïve to DMARD Treatment (EXPAND); Available from: https://clinicaltrials.gov/ct2/show/NCT05516979Administration, U.F.a.D. A Dose-range Study of the Safety and Efficacy of Treatment in Adult Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate (RESOLVE); Available from: https://clinicaltrials.gov/ct2/show/NCT05604885

The melanocortin system is one of the mammalian body's tools to regulate food intake in a push-pull fashion.{{cite journal | vauthors = Zhou Y, Rui L | title = Leptin signaling and leptin resistance | journal = Frontiers of Medicine | volume = 7 | issue = 2 | pages = 207–22 | date = June 2013 | pmid = 23580174 | pmc = 4069066 | doi = 10.1007/s11684-013-0263-5 }} The only neurons known to release melanocortins are located in the arcuate nucleus of the hypothalamus. However, [https://www.jidonline.org/article/S0022-202X(15)50783-5/pdf melanocortins are also produced by keratinocytes] in response to UV exposure. Accordingly, there is a subpopulation called POMC neurons and one called AgRP neurons. When POMC neurons release α-MSH, appetite is decreased. On the other hand, when AgRP neurons release AgRP, appetite is stimulated.

Leptin, the energy surfeit hormone, and Ghrelin, the hunger hormone, are upstream regulators of the melanocortin system in the brain.{{cite journal | vauthors = Klok MD, Jakobsdottir S, Drent ML | title = The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review | journal = Obesity Reviews | volume = 8 | issue = 1 | pages = 21–34 | date = January 2007 | pmid = 17212793 | doi = 10.1111/j.1467-789x.2006.00270.x | s2cid = 24266123 | doi-access = free }} These hormones also regulate the release of peptides other than the melanocortins. Disturbance of the leptin-melanocortin pathway can lead to early onset obesity as well as various metabolic disorders and suppressed immune function. {{cite journal | vauthors = Nunziata A, Borck G, Funcke JB, Kohlsdorf K, Brandt S, Hinney A, Moepps B, Gierschik P, Debatin KM, Fischer-Posovszky P, Wabitsch M | title = Estimated prevalence of potentially damaging variants in the leptin gene | journal = Molecular and Cellular Pediatrics | volume = 4 | issue = 1 | pages = 10 | date = November 2017 | pmid = 29101506 | pmc = 5670095 | doi = 10.1186/s40348-017-0074-x | doi-access = free }}

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• {{MeshName|Melanocortins}}

{{Hormones}}

{{Neuropeptides}}

{{Melanocortin receptor modulators}}

Category:Anterior pituitary hormones

Category:Peptide hormones

Category:Melanocortin receptor agonists