Melanotan II

Melanotan II (MT-II) is a synthetic cyclic 7-amino acid peptide developed at the University of Arizona as a shorter, more potent analog of α-MSH. Unlike Melanotan I (which is linear and MC1R-selective), Melanotan II is a cyclic peptide with non-selective activity across multiple melanocortin receptors: MC1R (tanning), MC3R (energy homeostasis), MC4R (sexual function, appetite), and MC5R (exocrine function). This broad receptor profile produces a combination of effects: skin darkening, increased sexual arousal and erectile function, appetite suppression, and facial flushing. MT-II became widely known through its sexual arousal effects, which led to the development of PT-141 (Bremelanotide/Vyleesi), a related compound that was specifically optimized for sexual function and received FDA approval. MT-II itself has never been approved by any regulatory agency and remains an unregulated research chemical, though it is widely used in self-administration for cosmetic tanning. Health authorities worldwide, including the FDA, EMA, TGA (Australia), and MHRA (UK), have issued warnings against MT-II due to safety concerns including unregulated manufacturing quality, potential cardiovascular effects, and risk of promoting melanocytic changes without medical supervision.

Melanotan II activates multiple melanocortin receptors due to its cyclic structure providing conformational flexibility for binding across the receptor family. At MC1R on melanocytes, it stimulates eumelanin synthesis through the cAMP/PKA/MITF pathway (identical to Melanotan I), producing skin darkening. At MC4R in the hypothalamus, MT-II activates pro-opiomelanocortin (POMC) neuron-mediated pathways that produce sexual arousal (through descending pathways to sacral parasympathetic neurons), appetite suppression (through POMC/CART anorexigenic signaling), and modulation of energy expenditure. The erectile/sexual arousal effect is centrally mediated; MT-II acts on hypothalamic MC4R to increase dopamine and oxytocin signaling in brain circuits controlling sexual response, which is distinct from the peripheral vascular mechanism of PDE5 inhibitors like sildenafil. At MC3R, MT-II influences energy homeostasis and cardiovascular regulation, which may contribute to flushing, blood pressure changes, and appetite effects. The non-selective receptor activation profile means MT-II produces a complex mixture of effects that cannot be individually titrated, contributing to its unpredictable side effect profile.