Everything below reports findings from cell cultures, isolated tissue and animals. This material is for research use only, not for human or veterinary use.
Melanotan I is a linear tridecapeptide built on alpha-melanocyte-stimulating hormone. Two substitutions separate it from the native chain. Norleucine replaces methionine at position 4. D-phenylalanine replaces L-phenylalanine at position 7.
Those two changes are the whole reagent. They raise potency at MC1R and they slow proteolysis [1]. Indexed clinical papers exist under the synonym afamelanotide. Those human endpoints sit outside this profile.
The useful laboratory questions are identity, receptor occupancy, and what animal pigment assays actually measured. Related cyclic chemistry sits in the Melanotan II profile.
Chemical identity
A linear tridecapeptide, capped at both ends, built on the alpha-MSH sequence with two deliberate substitutions.
| Property | Value |
|---|---|
| Sequence | Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 |
| Common names | Melanotan I, afamelanotide, NDP-alpha-MSH, CUV1647 |
| Molecular formula | C78H111N21O19 |
| Molecular weight | 1646.8 g/mol |
| Monoisotopic mass | 1645.8365 Da |
| CAS | 75921-69-6 |
| PubChem CID | 16197727 |
| InChIKey | UAHFGYDRQSXQEB-LEBBXHLNSA-N |
| Residues | 13 |
| Primary target | Melanocortin 1 receptor (MC1R) |
| Hydrogen-bond donors | 23 (PubChem computed) |
| Hydrogen-bond acceptors | 22 (PubChem computed) |
| Rotatable bonds | 51 (PubChem computed) |
| XLogP3-AA | -3.5 (PubChem computed) |
Reading the sequence
Both termini carry caps. An acetyl group sits on serine 1. The C-terminal valine ends as an amide rather than a free acid. Capping both ends removes the substrates that aminopeptidases and carboxypeptidases recognise. That is the standard reason a peptide survives longer in serum.
Nine of the thirteen residues match the native hormone exactly. The interesting chemistry sits at positions 4 and 7.
PubChem lists this chain as CID 16197727. The condensed sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. A certificate that quotes a free C-terminal acid, or a methionine at position 4, has named a different lot.
The two substitutions that define it
The native hormone carries methionine at position 4. That thioether oxidises. Norleucine replaces it with a straight butyl side chain that carries no sulfur. The substitution keeps roughly the same shape and bulk while removing the oxidation liability.
Both molecules carry phenylalanine at position 7. In the analogue it takes the D configuration. That single inversion changes the local backbone geometry. The resulting peptide resists the serum enzymes that clear the native hormone [1].
Everything the compound does differently follows from those two changes. The His-Phe-Arg-Trp pharmacophore shared by every melanocortin survives intact [15].
Native alpha-MSH still contains sulfur. Its formula is C77H109N21O19S and its mass sits near 1,664.9. Melanotan I drops that sulfur and adds the norleucine carbon count. Intact mass separates the pair at a glance.
Melanotan I was reverse-engineered from a degradation product
The design did not start on a drawing board. Sawyer and colleagues at Arizona were working with heat- and alkali-treated alpha-MSH (PMID 6777774). That preparation darkened frog skin for far longer than the fresh hormone, and nobody knew why [1].
Quantitative gas chromatography of the hydrolysed material gave the answer. The harsh treatment had partly racemised the peptide. The racemisation clustered at positions 4 and 7. Prolonged activity turned out to be a side effect of chemical damage.
So the group synthesised the damage on purpose. They made [Nle4]-alpha-MSH, which also gained prolonged activity after heat and alkali. Then they made [Nle4, D-Phe7]-alpha-MSH directly. The result resisted serum enzymes. It ran 26 times as potent as the native hormone in the mouse melanoma adenylate cyclase assay [1].
What ultralong meant on frog skin
The 1980 title claims ultralong biological activity. The claim is accurate against its comparator. Native alpha-MSH clears in minutes. Anything holding a frog skin dark for hours qualifies by that standard.
Read as a statement about a mammal, it means much less. A 2023 study injected an equivalent dose of the peptide into frogs and lost the pigment response within a few days. An acylated self-assembling version of the same molecule held the response beyond four weeks [16]. The word describes a comparison, not a calendar.
Frog-skin darkening is a melanocyte assay. It is not a use instruction. Write the species, the bath, and the duration on the same line.
The receptor and what binding it does
MC1R is a class A G protein-coupled receptor on melanocytes. Agonist binding raises cyclic AMP. That rise drives transcription of the pigment enzymes. It also shifts melanin synthesis toward eumelanin, the darker of the two polymers.
A solved structure
A 2021 paper reported three cryo-electron microscopy structures of the human MC1R-Gs complex (PMID 34453129) [15]. The first complex holds the native hormone. A second holds Melanotan I. A third holds the synthetic agonist SHU9119. Few compounds in this catalogue have a receptor complex solved with the compound itself in the pocket.
Two findings stand out. The conserved His-Phe-Arg-Trp motif occupies the orthosteric site in all three. That occupancy explains why melanocortin analogues resist selectivity engineering. A calcium ion also sits in the binding pocket, and ligand recognition depends on it. Most peptide receptors lack that ion [15].
If a laboratory wants to know whether a lot still presents that motif, the structure is the map. A deletion that removes histidine or tryptophan is a different reagent, even if the mass looks close on a low-resolution trace.
Potency at the human receptor
A Swiss group built a cell assay to test whether prolonged exposure raised neutralising antibodies [4]. The assay read cyclic AMP formation in a B16 mouse melanoma line transfected with the human receptor. It produced clean half-effective concentrations along the way: 38.8 plus or minus 10.6 nM for the native hormone, against 10.9 plus or minus 7.17 nM for the analogue [4].
Roughly a fourfold gap, well below the 26-fold figure from 1980. Different assay, different receptor species, different readout. Neither number contradicts the other. Neither describes potency in a person.
The antibody question itself came back negative in the sera that paper tested [4]. Indexed patient papers sit outside this profile. The transferable object is the transfected-cell EC50 pair.
MC1R signalling also has anti-inflammatory components in review [18]. That is why later groups ran small human pilots in other dermatology settings [2][3] and [6]. Those pilots are listed, not summarised as outcomes.
Animal pigmentation assays
Pigment chemistry is the biology this analogue was built to move. The assays that established it are animal and cell assays.
Frog skin and mouse melanoma cyclase
Sawyer’s 1980 paper is still the origin experiment [1]. Heat-alkali alpha-MSH darkened frog skin longer than the fresh hormone. The synthetic [Nle4, D-Phe7] chain then beat the native hormone 26-fold in mouse melanoma adenylate cyclase.
Those two readouts are not interchangeable. Frog skin is a tissue bath with an optical endpoint. Adenylate cyclase is an enzyme assay on melanoma membranes. Quote the assay with the number.
Chang later returned to frogs with the same sequence (PMID 37673364) [16]. A bolus of free peptide lost the pigment response within a few days. A gel-forming acylated analogue held melanogenesis beyond four weeks. Formulation, not sequence, set the duration in that comparison.
Free peptide versus a depot matrix
Melanotan I in solution and the same sequence in a slow-release matrix are not the same experiment. The frog work puts an equivalent dose of free peptide at a few days of response [16]. A matrix engineered to release slowly held it far longer.
Indexed human papers used a controlled-release implant. This profile does not treat that implant as a product. Bench work usually uses free peptide in buffer. A result obtained under one exposure profile does not transfer to the other without an argument.
A small-molecule comparator in animals
A non-peptidic MC1R agonist, dersimelagon, used Melanotan I as the reference comparator throughout its preclinical set (PMID 35665216) [12][18].
The small molecule showed nanomolar agonism at human MC1R and concentration-dependent melanin production in melanoma cells. Oral dosing darkened mouse coats from 0.3 mg/kg/day and pigmented monkey skin from 1 mg/kg/day, reversing after withdrawal [12].
Those milligram-per-kilogram figures belong to dersimelagon, not to this peptide. They still show what an MC1R agonist looks like in a coat-colour assay. They also show why a linear peptide and an oral small molecule are different reagents even when they share a receptor.
The opposite manipulation of the same pathway has its own catalogue entry. Glutathione sits on the depigmenting side of melanin chemistry. Those two reagents pair usefully for anyone studying the pigment switch from both directions.
Identity versus Melanotan II
Names in this family are close enough to swap by accident. Masses are not.
Mass and residue count
| Compound | Scaffold | Formula | Average mass |
|---|---|---|---|
| alpha-MSH | Linear 13-mer, Met4 | C77H109N21O19S | 1,664.9 |
| Melanotan I | Linear 13-mer, Nle4, D-Phe7 | C78H111N21O19 | 1,646.8 |
| Melanotan II | Cyclic 7-mer amide | C50H69N15O9 | 1,024.2 |
| PT-141 | Cyclic 7-mer acid | C50H68N14O10 | 1,025.2 |
Melanotan I is the linear tridecapeptide described here. Melanotan II is a cyclic heptapeptide with a lactam bridge. PT-141 is that cyclic chain with a free acid in place of the amide. Check the sequence in the methods, not the name in the title.
A 600 Da gap separates the linear peptide from the cyclic pair. Intact mass is the cheapest way to keep those literatures from contaminating each other.
Shared pharmacophore, different scaffold
All three synthetic ligands keep His-D-Phe-Arg-Trp [15]. Melanotan I keeps the rest of the alpha-MSH chain. The cyclic pair throws the chain away and locks the tetrapeptide in a lactam.
That is why selectivity differs. The linear analogue is biased toward MC1R. The cyclic amide hits MC1R, MC3R, MC4R, and MC5R together. Shared motif is not shared pharmacology.
Breindahl and colleagues assayed internet vials labelled as the cyclic sibling by LC-UV-MS/MS (PMID 24771717) [5]. Claimed content was 10 mg. Measured content ran from 4.32 mg to 8.84 mg. Two of three lots carried unidentified impurities at 4.1 to 5.9 percent. Those numbers describe Melanotan II. The method transfers. The masses do not.
Limits of the published record
Four gaps sit between the published record and the claims that circulate around this analogue.
What the indexed human papers are
Two randomised implant trials were published together in 2015 [8]. Observational series and regulator-requested cohorts followed [7][11]. Smaller pilots tested other dermatology settings [2][3] and [6]. Reviews cover the same indication family [9][13]. Dermoscopic follow-up of naevi and case collections of unregulated analogue use also sit in the file [10][14]. Trial-ethics and outcome-measure papers arrived later [17][19].
Those human endpoints are outside the scope of this profile. The papers remain cited so a reader can find them.
Implant papers are not solution papers
Almost every human study used a controlled-release implant. Bench work uses free peptide. Mixing the two exposure profiles is how this literature gets misquoted.
Which name was in the methods
Afamelanotide, NDP-alpha-MSH, CUV1647, and Melanotan I are the same sequence. Melanotan II is not. A paper that writes only “melanotan” has not identified the reagent.
What this profile will not do
It will not quote implant milligram figures, phototoxicity hours, or approval labels. Those sentences turn a research article into a use document.
How to read a Melanotan I study
Four questions separate the papers that are about this molecule from the papers that are not.
Which melanotan?
The names are close enough to swap by accident. Melanotan I is the linear tridecapeptide described here. Melanotan II is a cyclic heptapeptide. PT-141 is the deamidated cyclic relative. Check the sequence, then the mass.
Implant or solution?
Indexed human studies used a controlled-release implant [2][8] and [11]. Cell and frog work used free peptide [1][4] and [16]. A result obtained under one exposure profile does not transfer to the other without an argument.
Melanin or a clinical endpoint?
Pigmentation studies measure melanin density or adenylate cyclase. Those are laboratory endpoints. Clinical studies measure pain-free hours or quality-of-life scores [8][11]. Endpoint choice is why those papers do not pool with a frog-skin assay.
Assayed or assumed?
Case reports of unregulated analogue use almost never pair a dose with a content assay [10]. Breindahl’s LC-MS work on the cyclic sibling shows why that gap matters [5]. The reported milligram figure is what the label claimed.
Verifying research material
The peptide is a defined chemical entity with published identifiers, so verification is arithmetic rather than judgement.
Identity
Molecular formula C78H111N21O19 and monoisotopic mass 1645.8365 Da resolve to InChIKey UAHFGYDRQSXQEB-LEBBXHLNSA-N. Mass spectrometry should return an average mass near 1646.8. The practical precursor is the doubly charged ion, the same approach validated for its cyclic sibling [5].
Native alpha-MSH still carries sulfur and sits near 1,664.9. A lot that quotes that mass is not Melanotan I. A lot that quotes 1,024.2 is the cyclic amide instead.
Purity and stereochemistry
The D-phenylalanine at position 7 is the whole point of the molecule, and mass spectrometry cannot see it. An epimer at that position carries the same formula, the same mass, and the native hormone’s susceptibility to proteolysis. Chiral amino acid analysis after hydrolysis answers the question. It is the same technique that revealed the racemisation in 1980 [1].
Norleucine versus methionine is the other identity check. A methionine lot oxidises. A norleucine lot should not show the +16 Da methionine sulfoxide peak as a first impurity. Tryptophan and tyrosine oxidation remain live risks on this sequence.
Deletion sequences are the expected solid-phase impurity at thirteen residues. Reversed-phase chromatography with mass detection finds them. Ultraviolet detection alone often does not.
Handling
The sequence carries tryptophan and tyrosine, both of which absorb ultraviolet and photodegrade. Suppliers ship the material lyophilised for that reason. Store the powder cold, dry, and dark, and reconstitute close to the point of use.
Storage guidance is a house recommendation. Analytical documentation is per-lot release testing.
Reconstituted solutions of an unformulated peptide have none of the stabilisation a depot matrix provides [16]. Aliquot on reconstitution rather than sampling one vial repeatedly. Freeze-thaw cycling drives aggregation, which changes the species present without changing the label.
Adsorption to plastic is the routine loss at low concentration. The 51 rotatable bonds and the amphipathic sequence make that loss unsurprising. Peptide content differs from chromatographic purity. Acetate or trifluoroacetate content belongs on the certificate next to the free-base mass.
A second handling question is methionine bleed from a mis-made lot. Native alpha-MSH carries sulfur at position 4. This analogue should not. If intact mass shows 1,664.9 instead of 1,646.8, the vial holds the parent hormone. If it shows 1,024.2, the vial holds the cyclic amide. Run intact mass first, then a mapped digest, then a reversed-phase trace with a mass detector. That order finds the failures that a single HPLC area percent hides.
Counterion identity still changes the weighed mass. Trifluoroacetate from cleavage cocktails is common on research peptides. Acetate exchange, if it was done, belongs on the certificate. Do not infer the salt from the sequence.
Kimera publishes third-party certificates of analysis for every lot in its COA database. Laboratories source Melanotan I as an MC1R-biased linear alpha-MSH analogue. It sits beside Melanotan II, the cyclic non-selective relative, and PT-141, the deamidated cyclic acid. Related work appears in the peptides category.
Common questions about Melanotan I
Is Melanotan I the same sequence as afamelanotide? Yes. The same chain carries both names, along with NDP-alpha-MSH and the development code CUV1647.
How does it differ from alpha-MSH? Norleucine at position 4 and D-phenylalanine at position 7, plus acetyl and amide caps [1].
How does it differ from Melanotan II? Residue count and scaffold. This analogue is a linear 13-mer at 1,646.8 Da. Melanotan II is a cyclic 7-mer at 1,024.2 Da.
Is it selective for MC1R? More selective than its cyclic sibling. The shared His-Phe-Arg-Trp pharmacophore still makes selectivity a matter of degree across the family [15].
What animal assays established it? Frog-skin darkening and mouse melanoma adenylate cyclase in 1980, then later frog work on free versus acylated peptide [1][16].
Does this page report human outcomes? No. Indexed implant and pilot papers are listed so they can be found [8][11]. This profile stops at chemistry, receptor logic, and animal systems.
Summary of the evidence
Write the name, the mass, and MC1R on the first line of a notebook page. Everything else in this profile is a check on those three facts.
Identity: Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, C78H111N21O19, 1,646.8 Da, CAS 75921-69-6. PubChem CID 16197727 and InChIKey UAHFGYDRQSXQEB-LEBBXHLNSA-N close the record.
Design: a linear alpha-MSH analogue reverse-engineered from heat-alkali racemisation at positions 4 and 7 [1]. The His-Phe-Arg-Trp motif occupies the MC1R pocket with a bound calcium ion [15].
Cell potency: 10.9 nM against 38.8 nM for native alpha-MSH in a human-MC1R B16 cyclase assay [4]. The 1980 mouse melanoma cyclase gap was 26-fold [1].
Animal pigment: frog-skin darkening defined “ultralong” against a minutes-long native hormone [1]. Free peptide lost that response within days in frogs. An acylated depot analogue held it for weeks [16]. Dersimelagon later used this peptide as the MC1R comparator in mouse and monkey coat assays [12].
Limits: human implant outcomes, human adverse-event rates, and approval labels are out of scope here. Those papers remain in the reference list.
Status: supplied for laboratory research use only.
References
- Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A. 1980;77(10):5754-5758. PMID 6777774. DOI
- Haylett AK, Nie Z, Brownrigg M, Taylor R, Rhodes LE. Systemic photoprotection in solar urticaria with alpha-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-alpha-MSH. Br J Dermatol. 2011;164(2):407-414. PMID 20969564. DOI
- Böhm M, Ehrchen J, Luger TA. Beneficial effects of the melanocortin analogue Nle4-D-Phe7-alpha-MSH in acne vulgaris. J Eur Acad Dermatol Venereol. 2014;28(1):108-111. PMID 22845050. DOI
- Spichty R, Balimann M, Barman J, Minder EI. A bioassay for the detection of neutralizing antibodies against the alpha-melanocyte stimulating hormone analog afamelanotide in patients with erythropoietic protoporphyria. J Pharm Biomed Anal. 2013;75:192-198. PMID 23277150. DOI
- Breindahl T, Evans-Brown M, Hindersson P, McVeigh J, Bellis M, Stensballe A, Kimergård A. Identification and characterization by LC-UV-MS/MS of melanotan II skin-tanning products sold illegally on the Internet. Drug Test Anal. 2015;7(2):164-172. PMID 24771717. DOI
- Lim HW, Grimes PE, Agbai O, Hamzavi I, Henderson M, Haddican M, Linkner RV, Lebwohl M. Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: a randomized multicenter trial. JAMA Dermatol. 2015;151(1):42-50. PMID 25230094. DOI
- Biolcati G, Marchesini E, Sorge F, Barbieri L, Schneider-Yin X, Minder EI. Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. Br J Dermatol. 2015;172(6):1601-1612. PMID 25494545. DOI
- Langendonk JG, Balwani M, Anderson KE, Bonkovsky HL, Anstey AV, Bissell DM, Bloomer J, Edwards C, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med. 2015;373(1):48-59. PMID 26132941. DOI
- Lane AM, McKay JT, Bonkovsky HL. Advances in the management of erythropoietic protoporphyria: role of afamelanotide. Appl Clin Genet. 2016;9:179-189. PMID 28003770. DOI
- Habbema L, Halk AB, Neumann M, Bergman W. Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review. Int J Dermatol. 2017;56(10):975-980. PMID 28266027. DOI
- Wensink D, Wagenmakers MAEM, Barman-Aksözen J, Friesema ECH, Wilson JHP, van Rosmalen J, Langendonk JG. Association of afamelanotide with improved outcomes in patients with erythropoietic protoporphyria in clinical practice. JAMA Dermatol. 2020;156(5):570-575. PMID 32186677. DOI
- Suzuki T, Kawano Y, Matsumoto A, Kondo M, Funayama K, Tanemura S, Miyashiro M, Nishi A, Yamada K, Tsuda M, Sato A, Morokuma K, Yamamoto Y. Melanogenic effect of dersimelagon (MT-7117), a novel oral melanocortin 1 receptor agonist. Skin Health Dis. 2021;2(1):e78. PMID 35665216. DOI
- Wensink D, Wagenmakers MAEM, Langendonk JG. Afamelanotide for prevention of phototoxicity in erythropoietic protoporphyria. Expert Rev Clin Pharmacol. 2021;14(2):151-160. PMID 33507118. DOI
- Arisi M, Rossi M, Rovati C, Tomasi C, Mori L, Laini L, Calzavara-Pinton PG. Clinical and dermoscopic changes of acquired melanocytic nevi of patients treated with afamelanotide. Photochem Photobiol Sci. 2021;20(2):315-320. PMID 33721252. DOI
- Ma S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE. Structural mechanism of calcium-mediated hormone recognition and Gbeta interaction by the human melanocortin-1 receptor. Cell Res. 2021;31(10):1061-1071. PMID 34453129. DOI
- Chang CL, Cai Z, Hsu SYT. A gel-forming alpha-MSH analog promotes lasting melanogenesis. Eur J Pharmacol. 2023;958:176008. PMID 37673364. DOI
- Barman-Aksözen J, Andreoletti M, Blasimme A. Current trials in erythropoietic protoporphyria: are placebo controls ethical? Orphanet J Rare Dis. 2023;18(1):325. PMID 37845740. DOI
- Sato A, Morokuma K, Adachi T, Andou J, Miyashiro M, Suzuki T, Kawano Y, Kondo M, Ogasawara A, Ide M, Yamamoto Y. Discovery of MT-7117 (dersimelagon phosphoric acid): a novel, potent, selective, and nonpeptidic orally available melanocortin 1 receptor agonist. J Med Chem. 2024;67(24):21729-21748. PMID 39641249. DOI
- Dechant C, Wäscher S, Granata F, Gusset N, Pettersson M, Aksözen MH, Höglinger M, Falchetto R, Barman-Aksözen J. New pharmacotherapies for the erythropoietic protoporphyrias: an analysis of trial protocols from a patient perspective. Orphanet J Rare Dis. 2025;20(1):637. PMID 41466311. DOI
Melanotan I is sold for laboratory research use only. Not for human consumption, nor medical, veterinary, or household uses.
Literature retrieved from PubMed.
