Melanotan I (Afamelanotide)

Melanotan I (also known as Afamelanotide and approved as Scenesse) is a synthetic linear analog of alpha-melanocyte stimulating hormone (α-MSH). It was developed at the University of Arizona alongside Melanotan II, but as a linear tridecapeptide rather than a cyclic heptapeptide. The modifications at positions 4 (Nle replaces Met) and 7 (D-Phe replaces L-Phe) enhance potency and metabolic stability. MT-I is more selective for MC1R compared to MT-II, resulting in melanogenic effects with reduced activity at other melanocortin receptors. This selectivity led to its development as a prescription medication for erythropoietic protoporphyria (EPP), a rare genetic condition causing extreme photosensitivity.

Melanotan I acts primarily through MC1R activation: **Selective MC1R Agonism:** MT-I has approximately 100x greater selectivity for MC1R over MC3R/MC4R compared to MT-II. This results in melanogenic effects with minimal impact on sexual function, appetite, or cardiovascular parameters. **Melanogenesis Pathway:** MC1R activation on melanocytes increases intracellular cAMP, which activates CREB and upregulates MITF (melanocyte-inducing transcription factor). MITF increases expression of melanogenic enzymes including tyrosinase, TRP-1, and TRP-2, leading to increased melanin synthesis. **Eumelanin Shift:** Like α-MSH, MT-I promotes eumelanin (brown/black pigment) production over pheomelanin (red/yellow). This provides more effective UV protection than pheomelanin, which can actually generate reactive oxygen species under UV exposure. **Photoprotective Effects:** By increasing eumelanin content, MT-I provides enhanced protection against UV radiation damage, the basis for its approval in EPP patients who otherwise cannot tolerate sun exposure.