Melanocortin receptors explained

Melanocortins are a small group of signalling peptides that the body cuts from one large precursor protein called pro-opiomelanocortin (POMC). The best-known are α-MSH (alpha-melanocyte-stimulating hormone) and ACTH (adrenocorticotropic hormone), along with shorter fragments of them.

Think of POMC as a strip of stamps the body tears into pieces. Each piece carries a slightly different message, and where the message lands depends on which melanocortin receptor is there to receive it. Some of these natural fragments, and several lab-made peptides built to resemble them, are what the rest of this page is about.

There are five melanocortin receptors, each concentrated in different tissues:

• MC1R sits in skin and hair, where it controls pigment. Activating it pushes cells to make more of the dark pigment eumelanin, which is the basis of tanning.
• MC2R sits in the adrenal glands and responds to ACTH to drive cortisol production. It is the odd one out, it answers almost only to ACTH, not to α-MSH.
• MC3R and MC4R sit in the brain and govern appetite and energy balance. MC4R in particular is a master switch for hunger and bodyweight; rare faults in the MC4R gene are a known cause of severe early-onset obesity.
• MC5R sits in exocrine glands (such as sebaceous and sweat glands) and is linked to their secretions, though its role in humans is the least well mapped of the five.

Because these receptors are related but spread across very different organs, a peptide is rarely perfectly selective. Hit several at once and you get effects in several systems at once.

PT-141 (bremelanotide) acts centrally, in the brain rather than on the genitals, mainly through MC4R with some MC3R activity. By stimulating these receptors in regions involved in sexual motivation, it is thought to raise sexual desire rather than directly causing blood flow the way erectile-dysfunction drugs do. This central mechanism is what sets it apart, and we cover the distinction in central vs peripheral sexual function.

Bremelanotide is approved in the US, marketed as Vyleesi, for acquired, generalised hypoactive sexual desire disorder in premenopausal women. The same MC4R activity that drives desire also raises blood pressure and commonly causes nausea, which is why the approved label restricts how often it can be used. ✅ This is one of the few melanocortin peptides with a genuine regulatory approval behind it.

Melanotan II is a synthetic melanocortin built to be non-selective, it activates MC1R (hence the tanning effect) but also MC3R, MC4R and others. That broad reach is precisely the problem: alongside darker skin it can cause nausea, spontaneous erections, appetite changes and unpredictable darkening of moles.

💬 Melanotan II is not an approved medicine anywhere. It is sold illegally as an injectable "tanning" product, often unregulated and of unknown purity. UK and other regulators have repeatedly warned against it. It is the clearest example on this page of why hitting many melanocortin receptors at once is a liability, not a feature.

KPV is the very last three [amino acids](/glossary "Amino acid: The building blocks of proteins. A peptide is a short chain of them linked together.") (lysine-proline-valine) of α-MSH, its C-terminal fragment. It is interesting because its reported anti-inflammatory action appears to be largely melanocortin-receptor-independent, it seems to act inside cells on inflammatory signalling rather than by switching on MC1R–MC5R the way the parent hormone does.

🔬 This makes KPV a useful counter-example: a melanocortin-derived peptide that mostly sidesteps the receptor family. The evidence for it is preclinical, mostly cell and animal models, with no approved human use, so it should be read as an early research story rather than an established treatment. See our methodology for how we grade evidence like this.