Melanotan I Research, Specifications & Scientific Information

Introduction

Melanotan I is afamelanotide, and the two names sit on opposite sides of a boundary this page exists to keep clear. Under the second name it is the active substance of SCENESSE, a controlled-release implant approved by the U.S. Food and Drug Administration on 8 October 2019 and by the European Medicines Agency before that, for one rare disease. Under the first it circulates as a research chemical.

The molecule is the same. The approval is not about the molecule. It covers a particular finished product — a 16 mg implant released over months, manufactured and tested to a pharmaceutical standard — for adult patients with a history of phototoxic reactions from erythropoietic protoporphyria. A vial of peptide is not that product, and nothing established about that product in trials transfers to material supplied for laboratory use.

What is genuinely established is worth stating precisely, because it is unusually good evidence by the standards of this library: two multicentre randomised double-blind placebo-controlled trials, 168 participants between them, with a prespecified endpoint and published in the New England Journal of Medicine ^[1].

What Is Melanotan I?

Melanotan I is a synthetic thirteen-residue analogue of alpha-melanocyte-stimulating hormone, the endogenous peptide that drives pigment production in melanocytes. Its International Nonproprietary Name is afamelanotide; the chemical literature writes it as [Nle4, D-Phe7]-alpha-MSH and abbreviates it NDP-MSH; the development programme called it CUV1647.

Two substitutions separate it from the native hormone, and between them they account for its pharmacology:

• Norleucine replaces methionine at position 4. Methionine is the residue most readily oxidised in the native hormone, and removing it removes a degradation route.
• D-phenylalanine replaces L-phenylalanine at position 7. This is inside the His-Phe-Arg-Trp message sequence common to every melanocortin, and inverting the stereochemistry there holds the recognition core in a conformation that both resists proteolysis and binds more tightly.

The result is an agonist far more potent and far longer-lived than alpha-MSH itself. PubChem carries it under compound identifier 16197727, with CAS registry number 75921-69-6 and FDA/NCATS UNII code QW68W3J66U.

It is not the same compound as Melanotan II, which is a cyclic seven-residue analogue with a different structure, a different clinical history and no approval anywhere. The two are routinely conflated, and the distinction is set out in the comparison section below.

Melanotan I Specifications

Afamelanotide is alpha-melanocyte-stimulating hormone with two substitutions in the message sequence: norleucine replaces methionine at position 4, and D-phenylalanine replaces the L form at position 7. Those two changes are the whole of the design — they remove the oxidation-labile methionine and lock the recognition core in a conformation resistant to enzymatic degradation, which is why the analogue is far more potent and far longer-lived than the native hormone. It is written in the literature as [Nle4, D-Phe7]-alpha-MSH and abbreviated NDP-MSH. PubChem carries it under compound identifier 16197727 with CAS registry number 75921-69-6 and the FDA/NCATS UNII code QW68W3J66U; an acetate salt form has its own UNII, 1XCC161YKC, and material supplied as a reagent is commonly an acetate whose mass differs from the free-peptide figure above. Because position 7 is a D residue and position 4 is a non-standard residue, the single-letter code cannot express this sequence, and mass spectrometry cannot distinguish the D-Phe7 molecule from its all-L counterpart, which has a different pharmacology.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does Melanotan I Work?

The target is the melanocortin 1 receptor, MC1R, a class A G protein-coupled receptor expressed on melanocytes. Activation signals through Gs and cyclic AMP and shifts pigment synthesis toward eumelanin, the darker and more photoprotective of the two melanin types.

The chain from that receptor event to the approved indication runs through the disease rather than through cosmetic pigmentation, and it is worth following.

Erythropoietic protoporphyria is an inherited disorder of haem biosynthesis in which protoporphyrin IX accumulates. Protoporphyrin IX is a photosensitiser: it absorbs visible light — not ultraviolet, which is why conventional sunscreens are of limited value — and generates reactive species in the skin and in the cutaneous vasculature. The clinical consequence, as the trial report describes it, is a severe photodermatosis with acute phototoxicity, excruciating pain and markedly reduced quality of life ^[1].

Increased epidermal eumelanin absorbs some of that incident light before it reaches the accumulated porphyrin. The proposed mechanism of benefit is therefore an optical one at the level of tissue, not a correction of the underlying metabolic defect: the analogue does not reduce protoporphyrin IX, it changes how much light reaches it. That is consistent with the trial endpoint, which measured hours of light exposure before pain began rather than any biochemical marker.

Like every peptide built on the melanocortin message sequence, the compound is not selective between receptor subtypes. Structures of the melanocortin-4 receptor in complex with several ligands, this one among them, have resolved the conserved binding mode of peptide agonists at that subtype ^[4] — which is direct evidence that the molecule engages MC4R as well as MC1R.

Melanotan I Mechanism of Action

In vitro research

Receptor-level design. The Nle4 and D-Phe7 substitutions were made to produce a superpotent, degradation-resistant melanocortin agonist, and that history is documented in reviews of the melanocortin peptide field ^[8].

Structural biology at MC4R. Cryo-electron microscopy structures of the human melanocortin-4 receptor with bound ligands, including this analogue, resolved how peptide agonists are recognised at that receptor and how the receptor activates ^[4]. Two things follow. The binding mode of this molecule at a melanocortin receptor is now known at near-atomic resolution — a level of detail few compounds in this library have. And the fact that the structure exists at MC4R, not only at MC1R, confirms that a compound described clinically in terms of pigmentation is engaging receptors outside the skin.

What has not been characterised this way. No published structure of this analogue bound to MC1R, the receptor its approved indication depends on, was located. The pharmacology at MC1R is inferred from the compound's potency in pigmentation assays and from the melanocortin family's shared recognition motif rather than from a structure of that specific complex.

Findings in this section were obtained in receptor and structural systems. Nothing in them establishes anything about intact animals or about humans.

What Is Melanotan I Being Researched For?

• Erythropoietic protoporphyria — the indication the approval rests on, studied in two randomised placebo-controlled trials and in post-authorisation cohorts ^{[1, 5]}.
• X-linked protoporphyria — a closely related disorder, included alongside erythropoietic protoporphyria in quality-of-life cohort work ^[6].
• Other dermatological conditions — surveyed at review level as potential applications of an orphan-designated melanocortin agonist ^[7]. That survey describes research interest, not established indications.
• Melanocortin receptor structural pharmacology — where the compound appears as a reference ligand rather than as the subject ^[4].

Each of those is research into a pharmaceutical product candidate or an approved product, conducted under protocol in defined patient populations. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Human Research on Melanotan I

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The two registrational trials, 2015

Population. 168 adults with erythropoietic protoporphyria across two multicentre trials — 94 in the United States and 74 in the European Union — randomised 1:1 ^{[1, 2, 3]}.

Endpoint and duration. Subcutaneous implants containing 16 mg of afamelanotide or placebo every 60 days: five implants over 270 days in the European Union study, three over 180 days in the United States study. The primary efficacy endpoint was the number of hours of direct exposure to sunlight without pain. The type and duration of light exposure, the number and severity of phototoxic reactions, and adverse events were recorded throughout, with quality of life assessed by validated questionnaires and photoprovocation testing in a United States subgroup ^[1].

Result. In the United States study, median pain-free time at six months was 69.4 hours against 40.8 hours on placebo (p = 0.04). In the European Union study, median pain-free time at nine months was 6.0 hours against 0.8 hours (p = 0.005), and phototoxic reactions numbered 77 against 146 (p = 0.04). Quality of life improved in both trials ^[1].

Adverse events. Mostly mild. Serious adverse events were not considered related to the study drug ^[1].

Limitations. The two trials produced medians an order of magnitude apart on the same endpoint — 69.4 against 40.8 hours in one, 6.0 against 0.8 in the other — because they ran over different periods, at different latitudes, with different numbers of implants and different amounts of available sunlight. The difference is a caution about quoting either absolute figure as the size of the effect. The trials were funded by the product's manufacturer, which is stated in the report. And both are modest in size, as trials in a rare disease necessarily are.

After authorisation

Observational cohorts. A German cohort study has investigated short- and long-term safety and clinical effectiveness of the 16 mg implant in erythropoietic protoporphyria under normal conditions of use ^[5]. A retrospective cohort has examined the association between quality-of-life measures and treatment in erythropoietic protoporphyria and X-linked protoporphyria ^[6].

What this kind of evidence can and cannot do. Post-authorisation observation is how a rare-disease product accumulates a safety record across years that a 270-day trial cannot reach. It is not randomised, and effectiveness estimates from it carry the selection effects of who receives the product and who stays on it.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

Melanotan I vs Related Compounds

Against Melanotan II

Melanotan II is the compound most often confused with this one, and almost nothing transfers between them. This is a linear thirteen-residue analogue of the full hormone with an approved finished product behind it. That is a cyclic seven-residue analogue closed by a lactam bridge, never approved in any jurisdiction, whose human research record consists of small studies from the 1990s. A statement true of one is not, by default, true of the other.

Against PT-141

PT-141 (bremelanotide) is a further modification of the cyclic Melanotan II scaffold, developed for a different indication and approved in the United States for it. All three share the His-Phe-Arg-Trp melanocortin message sequence; they differ in ring structure, terminal chemistry, receptor potency ordering and regulatory position.

Against native alpha-MSH

The native hormone is cleared within minutes and oxidises at its methionine. The two substitutions that define this analogue exist to remove both problems ^[8], which is why the analogue is used in research and the native peptide is not.

What the approval is specific to

SCENESSE is a 16 mg controlled-release implant. The trial results were generated with that implant, administered at 60-day intervals, not with bolus administration of a peptide solution. Approval attaches to the product, the route and the indication together, and none of those three is a property of a research-grade powder.

No comparison of effect between these compounds is made on this page.

Chemical & Molecular Characteristics

Afamelanotide is a linear thirteen-residue peptide, N-terminally acetylated and C-terminally amidated, with molecular formula C78H111N21O19 and average mass 1646.8 g/mol under PubChem compound identifier 16197727.

The sequence cannot be written in single-letter code. Position 4 is norleucine, which has no single-letter representation, and position 7 is the D enantiomer of phenylalanine, which single-letter code cannot distinguish from the L form at all. Any listing that gives this molecule as a plain string of capital letters is describing a different compound.

Mass spectrometry cannot confirm the stereochemistry. D-phenylalanine and L-phenylalanine are identical in mass. A mass-spectrometric result matching 1646.8 daltons is consistent with the intended molecule and equally consistent with its all-L counterpart, which has different receptor pharmacology. Establishing the D configuration requires chiral analysis, not a mass measurement — and this is the single most consequential analytical point about the compound.

Both termini are blocked. The N-terminal acetyl and the C-terminal amide remove the charges that exopeptidases and ion-exchange methods rely on. They contribute to the molecule's stability and they change its chromatographic behaviour relative to an unblocked peptide of the same sequence.

Tryptophan and tyrosine give it a usable chromophore, and a liability. The single tryptophan at position 9 and the tyrosine at position 2 make the peptide readily quantified at 280 nm, unlike many of the short peptides in this library. Tryptophan is also the residue most vulnerable to oxidation and photodegradation, and its oxidation products are close in mass and often poorly resolved from the parent.

Salt form changes the figure on a certificate. An acetate salt has its own UNII, 1XCC161YKC, and reagent-grade material is commonly an acetate or trifluoroacetate salt. A measured mass or a percentage purity that does not state the counter-ion and the water content is incomplete.

Frequently Asked Questions

Scientific References

1. Langendonk JG, Balwani M, Anderson KE, et al.. Afamelanotide for Erythropoietic Protoporphyria The New England journal of medicine; 2015. PMID 26132941 doi:10.1056/NEJMoa1411481
2. Phase III Confirmatory Study in Erythropoietic Protoporphyria 2012. NCT01605136
3. Phase III Confirmatory Study in Erythropoietic Protoporphyria (EPP) 2009. NCT00979745
4. Zhang H, Chen LN, Yang D, et al.. Structural insights into ligand recognition and activation of the melanocortin-4 receptor Cell research; 2021. PMID 34433901 doi:10.1038/s41422-021-00552-3
5. Homey B, Schelonke K, Schlegel CM, et al.. German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP) Photodermatology, photoimmunology & photomedicine; 2025. PMID 40082741 doi:10.1111/phpp.13012
6. Ceresnie MS, Mohney L, Ko D, et al.. Association of quality of life measures with afamelanotide treatment in patients with erythropoietic protoporphyria and x-linked protoporphyria: A retrospective cohort study Journal of the American Academy of Dermatology; 2023. PMID 36244556 doi:10.1016/j.jaad.2022.10.012
7. Wu J, Cotliar R. Afamelanotide: An Orphan Drug with Potential for Broad Dermatologic Applications Journal of drugs in dermatology : JDD; 2021. PMID 33683075 doi:10.36849/JDD.5526
8. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization Peptides; 2006. PMID 16412534 doi:10.1016/j.peptides.2005.01.029

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.