# Melanotan II

Melanotan II is a synthetic analogue of the peptide hormone α-melanocyte-stimulating hormone (α-MSH) that stimulates melanogenesis to facilitate tanning. It may also increase sexual arousal.
It was developed as a successor to afamelanotide ("Melanotan I"), an FDA-approved drug operating through a similar pathway. Clinuvel Pharmaceuticals intended to offer it as a cosmetic, but abandoned this pursuit in the 2000s due to regulatory restrictions and concerns about the promotion of suntanning. Unlicensed Melanotan II is found on the internet, although health agencies advise against its use due to legality and a lack of testing.
Melanotan-II may cause reversible darkening of moles and freckles. It is unclear if Melanotan II can increase (or reduce) the risk of developing melanoma, because reports of melanomas associated with its use have coincided with heavy UV exposure and sun bed use. A 2013 scientific review found there was no conclusive evidence it causes melanoma, and a 2021 review concluded "the increased risk of melanoma in Melanotan users, who use it for tanning and exhibit sun-seeking behaviour, can probably be explained by more UV exposure".
Side effects may include facial flushing, nausea and erection in males.

## Synthesis

In the synthesis of melanotan II, an ε-amino group of lysine and an γ-carboxy group of aspartic acid have their orthogonal protection removed before undergoing a carbodiimide mediated lactamization, leading to an intermediate. This intermediate, when attached to N-acetylnorleucine, forms melanotan II. The entire process can be accomplished in 12 steps with an overall yield of 2.6%, and the product is more than 90% pure without preparative chromatography.

## Mechanism of action

Melanotan II acts as a non-selective agonist of the melanocortin receptors MC$_1$, MC$_3$, MC$_4$, and MC$_5$.
Melanotan II produces melanogenesis by activation of the MC$_1$ receptor, whereas its clinically documented sexual effects are thought to be related to its ability to activate the MC$_4$ receptor (though the MC$_3$ is thought to also possibly be involved).
Other effects of melanotan II, mostly regarded as adverse effects, include flushing, nausea, vomiting, stretching, yawning, and loss of appetite (the last via activation of MC$_4$).

## History and research

Research in the early 1960s showed that in rats, administration of α-MSH caused sexual arousal, and work on this continued in many labs up through the 1980s, when scientists at the University of Arizona began attempting to develop α-MSH and analogs as potential sunless tanning agents, and synthesized and tested several analogs, including melanotan-I and melanotan II.
Early in the research process one of the scientists, who was conducting experiments on himself with an early tool compound, melanotan II, injected himself with twice the dose he intended to and got an eight-hour erection, along with nausea and vomiting.
As a tanning agent, melanotan I (now known as afamelanotide) was licensed by Competitive Technologies, a technology transfer company operating on behalf of the University of Arizona, to an Australian startup called Epitan, which changed its name to Clinuvel in 2006. Afamelanotide was approved by the FDA in 2019.
As a sexual dysfunction agent, melanotan II was licensed by Competitive Technologies to Palatin Technologies. Palatin ceased development of melanotan II in 2000 and synthesized, patented, and began to develop bremelanotide, a likely metabolite of melanotan II that differs in that it has a carboxy group where melanotan II has an amide.
Clinuvel Pharmaceuticals intended to offer it as a cosmetic, but abandoned this pursuit in the 2000s.
Competitive Technologies (Clinuvel) sued Palatin for breach of contract and tried to claim ownership of bremelanotide; the parties settled in 2008 with Palatin retaining rights to bremelanotide, returning rights to melanotan II to Competitive Technologies, and paying US$800,000.
Melanotan-II may cause reversible darkening of moles and freckles. It is unclear if Melanotan II can increase (or reduce) the risk of developing melanoma. Reports of melanomas associated with the use of Melanotan II have coincided with heavy sunbathing and sun bed use. A 2013 scientific review found there was no conclusive evidence it causes melanoma, and a 2021 review concluded "the increased risk of melanoma in Melanotan users, who use it for tanning and exhibit sun-seeking behaviour, can probably be explained by more UV exposure". A 2020 in vivo study found that Melanotan II suppressed the progression of melanomas.

## Society and culture

Numerous products are sold online and in gyms and beauty salons as "melanotan" or "melanotan-1" or "melanotan-2" in their marketing.
The unregulated products are not legal to be sold for human usage in any jurisdiction.
Starting in 2007, health agencies in various countries began issuing warnings against their use.