Afamelanotide vs Melanotan II
Afamelanotide and Melanotan II are synthetic α-MSH analogues that act at melanocortin receptors. Afamelanotide is FDA-approved for erythropoietic protoporphyria; Melanotan II is unapproved. This page compares their structures, receptor selectivity, evidence, regulatory status and analytics.
Both peptides came from research at the University of Arizona in the 1980s and 1990s that sought stabilized analogues of α-melanocyte-stimulating hormone (α-MSH) able to stimulate melanin production. Afamelanotide, originally called Melanotan I, is a linear 13-residue analogue. Melanotan II is a shorter cyclic analogue built around the same core pharmacophore.
Their paths diverged sharply. Afamelanotide was developed through controlled clinical trials and approved by the FDA in 2019 as Scenesse for adults with erythropoietic protoporphyria. Melanotan II was never approved; its broader receptor activity led to the related compound bremelanotide, while unlicensed tanning products sold under the melanotan name have drawn regulator warnings.
Side-by-side
| Attribute | Afamelanotide | Melanotan II |
|---|---|---|
| Also known as | Melanotan I; [Nle4, D-Phe7]-α-MSH; NDP-MSH | MT-II |
| Structure | Linear 13 residues; full α-MSH length with Nle4 and D-Phe7; N-acetyl, C-amide | Cyclic 7 residues; lactam bridge Asp–Lys; Nle and D-Phe; N-acetyl, C-amide |
| Receptor profile | Potent MC1R agonist; also active at other melanocortin receptors | Non-selective agonist at MC1R, MC3R, MC4R and MC5R |
| Research areas | Photoprotection in photodermatoses, especially erythropoietic protoporphyria | Pigmentation, sexual function and appetite in animal and early human studies |
| Evidence level | Approved (phase 3 trials in erythropoietic protoporphyria) | Early-clinical; small studies only |
| FDA status | Approved 2019 as Scenesse for erythropoietic protoporphyria | Not approved by the FDA or any other regulator; subject of public warnings |
| Related compounds | Native α-MSH | Bremelanotide (PT-141), its C-terminal acid analogue |
| WADA | Check the current WADA Prohibited List | Check the current WADA Prohibited List |
| Analytical pitfalls | Tryptophan oxidation; correct D-Phe stereochemistry; longer sequence impurities | Confirming cyclization; distinguishing from bremelanotide by mass; tryptophan oxidation |
| Storage | Lyophilized at -20 °C, protected from light and moisture | Lyophilized at -20 °C, protected from light and moisture |
Linear vs cyclic design
Afamelanotide keeps the full 13-residue length of α-MSH but replaces methionine 4 with norleucine to remove an oxidation site and phenylalanine 7 with D-phenylalanine, which increases potency and resistance to proteases. Melanotan II trims the sequence down to the His-D-Phe-Arg-Trp core and ties it into a ring through a lactam bridge between aspartic acid and lysine side chains. Cyclization constrains the conformation and changes how the peptide engages different melanocortin receptor subtypes.
Receptor selectivity and its consequences
Afamelanotide acts strongly at MC1R, the receptor on melanocytes that drives eumelanin production, which suited its development for photoprotection. Melanotan II activates MC1R as well as MC3R and MC4R, receptors in the brain linked to appetite and sexual function, so early human studies reported effects beyond pigmentation, including on erectile function and nausea. Those observations led to bremelanotide, compared in PT-141 vs Melanotan II. Effects reported in small studies of Melanotan II are not established clinical findings.
Regulatory contrast
Afamelanotide's approval rests on randomized trials in erythropoietic protoporphyria, a rare condition causing severe pain on light exposure, with outcomes based on time tolerated in sunlight; the approved product is a controlled-release implant. Melanotan II has no approval anywhere. Regulators including the FDA, the UK MHRA and Australia's TGA have warned that unlicensed products sold as melanotan have unknown safety, quality and contents. Approved afamelanotide data say nothing about the quality of research-grade material.
Analytical notes
Both peptides contain tryptophan, so oxidized species should be monitored. Their D-phenylalanine is essential for activity, and standard HPLC and mass spectrometry do not confirm stereochemistry; chiral methods are needed to detect epimers. For Melanotan II, mass spectrometry should confirm the cyclized structure, since the linear precursor differs by the mass of water, and should distinguish it from bremelanotide, which has a free C-terminal acid instead of an amide.
Frequently asked questions
Is afamelanotide the same as Melanotan I?
Yes. Afamelanotide is the nonproprietary name for the compound originally called Melanotan I, the linear α-MSH analogue [Nle4, D-Phe7]-α-MSH. It is approved by the FDA as Scenesse for adults with erythropoietic protoporphyria. Melanotan II is a different, cyclic and less selective analogue that has never been approved.
Is Melanotan II FDA approved?
No. Melanotan II is not approved by the FDA or any other regulator. The FDA, the UK MHRA and Australia's TGA have warned the public about unlicensed tanning products sold as melanotan. The only approved melanocortin peptides in this family are afamelanotide (Scenesse), bremelanotide (Vyleesi) and setmelanotide (Imcivree), each for a specific indication.
Why do afamelanotide and Melanotan II have different effects?
The difference comes mainly from receptor selectivity. Afamelanotide acts strongly at MC1R, which controls melanin production in skin. Melanotan II also activates MC3R and MC4R in the brain, which are involved in appetite and sexual function. Its cyclic structure constrains the peptide in a way that broadens its activity across receptor subtypes.
Full entries
- Afamelanotide
Afamelanotide is a synthetic 13-amino-acid analogue of α-melanocyte-stimulating hormone, [Nle4, D-Phe7]-α-MSH, that activates the melanocortin 1 receptor. It is FDA-approved as Scenesse (2019) for erythropoietic protoporphyria.
- Melanotan II
Melanotan II is a synthetic cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone that activates several melanocortin receptors. It is not approved as a medicine anywhere, and regulators have warned about unlicensed tanning products.
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