Melanotan I

Overview

Melanotan I — known in its approved form as afamelanotide — is a synthetic analogue of alpha-melanocyte-stimulating hormone. It is the most conservative of the melanocortin analogues covered here: where the others truncate, cyclise or fragment the parent hormone, this one keeps essentially all of it.

It is not part of our catalogue. It is documented because the melanocortin compounds only make sense as a set, and this is the member that anchors one end of it.

Chemical identity

• Also known as: afamelanotide, [Nle⁴, D-Phe⁷]-α-MSH, NDP-MSH
• CAS number: 75921-69-6
• Molecular formula: C₇₈H₁₁₁N₂₁O₁₉
• Molecular weight: 1646.8 g/mol
• Classification: Linear alpha-MSH analogue, MC1R-preferring agonist
• Length: 13 residues

At 1,647 g/mol it sits above the point where a two-dimensional structure diagram stays readable, so the composition is described rather than drawn.

Two substitutions, no restructuring

Alpha-MSH is thirteen residues. Melanotan I is those same thirteen residues with two changes:

• Position 4: methionine to norleucine. Methionine oxidises readily, which limits shelf life and can inactivate the peptide. Norleucine is nearly identical in shape and hydrophobicity but has no sulfur, so it cannot oxidise.
• Position 7: L-phenylalanine to D-phenylalanine. The mirror-image form resists proteolysis, and in this position it also increases receptor affinity substantially.

That is the entire modification. No residues removed, no ring closed, no chain shortened — which is why the alternative name, NDP-MSH, simply records the two substitutions.

Linear where Melanotan II is cyclic

The structural contrast with Melanotan II is the useful thing to understand here, because it produced two compounds with different selectivity from the same starting point.

Melanotan II takes the receptor-binding core, cyclises it into a rigid macrocycle, and discards the rest. Rigidity increases potency, but the resulting shape fits all four relevant melanocortin receptors well — which is why it affects pigmentation, appetite and sexual function simultaneously.

Melanotan I stays linear and keeps the full sequence. It retains more of the parent hormone’s own receptor preference, favouring MC1R, and does not carry the same central activity.

The lesson generalises beyond these two molecules: constraining a peptide’s conformation raises potency, and can just as easily broaden selectivity as narrow it. Rigidity is not automatically precision.

The melanocortin family, complete

With this compound the set documented in this library is complete, and the four together map one hormone onto its receptors:

• Melanotan I — full-length, linear, two substitutions. MC1R-preferring; pigmentation.
• Melanotan II — cyclic heptapeptide from the core. Non-selective across MC1R, MC3R, MC4R, MC5R.
• PT-141 — Melanotan II’s deamidated metabolite. MC4R-preferring; central effects.
• KPV — the C-terminal tripeptide. Anti-inflammatory, no receptor-mediated pigmentation.

Four molecules from one thirteen-residue hormone, each retaining a different part of its activity depending on which part of the sequence was kept and how it was shaped.

Regulatory status

Afamelanotide is an approved prescription medicine in the European Union and the United States, indicated for erythropoietic protoporphyria — a rare inherited disorder in which a defect in haem synthesis causes severe pain on exposure to light.

The mechanism is directly related to what the compound does: increasing eumelanin in the skin provides photoprotection, reducing the light exposure that triggers symptoms. It is one of the few instances where a melanocortin agonist’s pigmentation effect is the therapeutic goal rather than a side effect.

The approved product is an implant formulation, which is worth noting because it differs from how the compound appears in research contexts.

Reported observations

Trial literature reports nausea, flushing and headache as the common findings — the pattern shared across melanocortin agonists — along with the expected darkening of skin and of existing pigmented lesions.

The pigmentary effects deserve the same attention here as on the Melanotan II page. Increasing melanocyte activity is what this compound does, and monitoring of pigmented lesions features in the clinical literature for that reason rather than as a formality.

Handling, reconstitution and storage

• No methionine. The norleucine substitution removes the oxidation-prone residue entirely, making this more storage-stable than native alpha-MSH.
• The single tryptophan remains photosensitive, so protection from light is still warranted.
• Less rigid than Melanotan II. A linear thirteen-residue peptide has more conformational freedom than a macrocycle and is correspondingly more vulnerable to mechanical stress. Do not shake.
• Lyophilised storage: sealed, refrigerated, protected from light; freeze for long-term storage.

Purity and analytical verification

The verification question specific to this compound concerns its two substitutions, and one is considerably easier to check than the other.

Norleucine for methionine changes the formula: methionine contains sulfur and norleucine does not. A batch made with methionine at position 4 would differ in both elemental composition and mass, and would be detectable. The absence of sulfur in the formula above is itself confirmation that the substitution is present.

D-phenylalanine for L-phenylalanine is invisible to mass spectrometry — the same problem described for Mod GRF 1-29. Enantiomers have identical formulae and identical masses. A batch synthesised with the L form would weigh exactly the same while binding its receptor far less well, and no routine certificate would show it.

That asymmetry is worth internalising: one substitution is confirmed by a number on a certificate, the other is not confirmable by any test a supplier is likely to have run.

References

• Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. New England Journal of Medicine, 2015. PMID 26132941
• Dorr RT, Dvorakova K, Brooks C, et al. Increased eumelanin expression and tanning is induced by a superpotent melanotropin [Nle⁴-D-Phe⁷]-alpha-MSH in humans. Photochemistry and Photobiology, 2000. PMID 11045725

Summary

Melanotan I (afamelanotide, NDP-MSH) is a linear thirteen-residue analogue of alpha-MSH, CAS 75921-69-6, molecular formula C₇₈H₁₁₁N₂₁O₁₉, molecular weight 1,646.8 g/mol. Two substitutions — norleucine for methionine at position 4 and D-phenylalanine at position 7 — give stability and receptor affinity without restructuring the molecule. It favours MC1R and lacks the broad receptor engagement of the cyclic Melanotan II, illustrating that conformational rigidity raises potency without necessarily narrowing selectivity. It is approved as a prescription medicine for erythropoietic protoporphyria, where its pigmentation effect is the therapeutic mechanism. We do not stock it.

This page is provided for research reference. Compounds described in this library are for laboratory research use only, are not drugs, foods or cosmetics, and may not be used for any purpose other than in vitro or non-human laboratory research.