Melanotan I vs Melanotan II vs PT-141: Three Melanocortin Analogs Compared

Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.

Melanotan I, Melanotan II and PT-141 are all synthetic analogs of alpha-melanocyte-stimulating hormone (alpha-MSH), and two of them differ by a single atom. This article compares the three by structure (linear versus cyclic), receptor selectivity across the melanocortin family, which ones became approved drugs and under what names, and what a research certificate has to show to tell them apart.

The short answer: one linear 13-mer and two cyclic 7-mers

Melanotan I is a linear 13-residue analog of alpha-MSH with two substitutions, norleucine at position 4 and D-phenylalanine at position 7. Melanotan II is a 7-residue fragment of that analog cyclized through a lactam bridge between side chains. PT-141 is Melanotan II with its C-terminal amide replaced by a free carboxylic acid. Melanotan I is approved by the FDA as Scenesse under the name afamelanotide. PT-141 is approved by the FDA as Vyleesi under the name bremelanotide. Melanotan II has never been approved anywhere and is the subject of regulator warnings in several countries.

A research vial of any of the three is not the approved product. The compound-level articles on Melanotan I and II and PT-141 go deeper on each; this article is about what separates them.

The alpha-MSH scaffold and the Nle4, D-Phe7 substitutions

Native alpha-MSH is Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂, a 13-residue product of pro-opiomelanocortin with an average mass near 1,665 Da. The residues His-Phe-Arg-Trp at positions 6 through 9 are the "message" motif that melanocortin receptors recognize. A 1980 Proceedings of the National Academy of Sciences paper by Sawyer, Hruby and colleagues reported that replacing Met4 with norleucine and Phe7 with its D-enantiomer produced an analog, [Nle4, D-Phe7]-alpha-MSH, that resisted serum enzymes and showed prolonged, strongly increased activity in frog-skin bioassays, mouse melanoma adenylate cyclase assays and mouse melanoma tyrosinase assays. That analog is Melanotan I, later named afamelanotide, with an average mass near 1,647 Da. Norleucine removes the oxidation-prone methionine sulfur; D-Phe7 stabilizes the turn conformation at the message motif and blocks proteolysis.

A 1997 Journal of Medicinal Chemistry paper by Haskell-Luevano and colleagues characterized NDP-MSH as having nanomolar efficacy at every human melanocortin receptor subtype except MC2R, the ACTH-only receptor, which is the key point about Melanotan I: it is potent but not subtype-selective across MC1R, MC3R, MC4R and MC5R.

Linear versus cyclic: the lactam bridge that makes Melanotan II

Melanotan II is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂, a 7-residue fragment corresponding to alpha-MSH positions 4 through 10 in which the Glu5 and Gly10 of the native sequence are replaced by Asp and Lys, and the Asp side-chain carboxyl is joined to the Lys side-chain amine to form a lactam ring. Its molecular formula is C₅₀H₆₉N₁₅O₉, average mass about 1,024 Da. The 1989 Journal of Medicinal Chemistry paper by Al-Obeidi, Hadley, Hruby and colleagues that introduced the cyclic lactam series describes the design as based on molecular dynamics and reports potent and prolonged activity in frog and lizard skin bioassays, with the Asp5-Lys10 ring size and the D-Phe7 substitution together accounting for the gain.

Cyclization does two things chemically. It locks the His-D-Phe-Arg-Trp message into a turn, and it removes the two free termini and the flexible N- and C-terminal segments that proteases attack. The cost is selectivity: a 2022 Journal of Medicinal Chemistry paper by Tomassi and colleagues, which replaced the lactam with xylene-derived thioether linkers, describes the parent Melanotan II as "a potent and unselective agonist" of human melanocortin receptors and shows that changing only the ring linker shifts the subtype profile, which is direct evidence that the lactam geometry itself sets the selectivity.

One atom apart: Melanotan II and PT-141

PT-141 (bremelanotide) is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH. It is Melanotan II with the C-terminal primary amide replaced by a carboxylic acid, which adds one mass unit (about 1,025 Da versus 1,024 Da) and one negative charge at neutral pH. A 2004 Current Opinion in Investigational Drugs profile by Hedlund records that Palatin developed PT-141 as a modified analog of "PT-14," the company's designation for Melanotan II. The 2020 Annals of Pharmacotherapy review by Mayer and Lynch, written after approval, describes bremelanotide as a melanocortin-4 receptor agonist, and earlier pharmacology from the Palatin program characterized it as an agonist at MC3R and MC4R with binding at MC1R as well.

One mass unit is within the resolving power of any modern mass spectrometer but is easy to miss on a certificate that reports only a nominal mass, and the two compounds co-elute closely on reverse-phase HPLC. A certificate for either should report an observed monoisotopic mass to at least one decimal place and should state whether the C-terminus is an amide or an acid.

Side-by-side comparison

The table makes the regulatory asymmetry visible. The oldest and newest molecules in the set are approved drugs; the one in the middle, from which PT-141 was derived, is not.

Receptor selectivity across the melanocortin family

There are five melanocortin receptors, all class A G-protein-coupled receptors signaling through G_s and cyclic AMP. MC1R is expressed on melanocytes, MC2R responds only to ACTH, MC3R and MC4R are expressed in the central nervous system, and MC5R in exocrine tissue. None of the three analogs discriminates sharply among MC1R, MC3R, MC4R and MC5R in binding assays; the differences are in relative potency. Afamelanotide's pharmacology is framed around MC1R, as the 2017 Clinical Pharmacokinetics review by Minder and colleagues sets out, because that is the receptor on the cell type relevant to its indication, not because it is MC1R-selective. Bremelanotide is framed around MC4R for the same reason. Melanotan II is simply non-selective. The article on KPV describes the C-terminal alpha-MSH tripeptide, which lacks the message motif entirely and is studied for different reasons.

Which became approved products, and where

Afamelanotide was approved in the European Union in 2014 as a controlled-release implant for erythropoietic protoporphyria, as the 2016 American Journal of Clinical Dermatology review by Kim and Garnock-Jones records, and was approved by the FDA as Scenesse in 2019. Bremelanotide was approved by the FDA as Vyleesi in 2019. Melanotan II was never carried through an approval program; a 2009 BMJ letter by Evans-Brown and colleagues documented its unlicensed availability in the general population and the resulting warnings from medicines regulators. Rodent work continues, for example a 2003 European Journal of Pharmacology study by Ter Laak and colleagues in a rat sciatic nerve model, but none of it is an approval pathway.

For a laboratory the point is this: a lyophilized vial labeled afamelanotide or bremelanotide shares a sequence with Scenesse or Vyleesi but is not that product, is not made to that product's specification, and carries only its own certificate. The article on why one peptide has five names uses PT-141/bremelanotide as a worked example of code name, INN and trade name.

What a certificate must show for each

For Melanotan I the identity line should show a mass near 1,647 Da and the chromatogram should be free of the +16 Da oxidation peak that native alpha-MSH gives at Met4; norleucine removes that liability, so an oxidation peak on a Melanotan I certificate suggests the wrong sequence. For Melanotan II and PT-141 the identity line must distinguish 1,024 from 1,025 Da and the certificate must state amide versus acid. All three contain tryptophan, which is light-sensitive and shows a characteristic +16 and +32 Da oxidation pattern, and all three contain D-Phe, whose configuration mass spectrometry cannot confirm. US Prime Peptides posts lot-matched certificates for MT-1 (Melanotan I) 10 mg, MT-2 10 mg and PT-141 10 mg before purchase, each with mass-spectrometry identity, HPLC purity, net peptide content, endotoxin, sterility and heavy-metals results from an independent US laboratory.

Frequently Asked Questions

What is the difference between Melanotan II and PT-141?

One atom's worth of structure. Both are Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]; Melanotan II ends in a C-terminal amide and PT-141 ends in a free carboxylic acid. The masses differ by about 1 Da (1,024 versus 1,025 Da), and PT-141 carries one extra negative charge at neutral pH.

Is Melanotan I the same as afamelanotide?

Yes. Melanotan I is the original name for [Nle4, D-Phe7]-alpha-MSH, the linear 13-residue analog first reported in 1980. Afamelanotide is its international nonproprietary name, and Scenesse is the trade name of the product approved by the FDA in 2019.

Which melanocortin analogs are approved by the FDA?

Afamelanotide (Melanotan I) is approved by the FDA as Scenesse, and bremelanotide (PT-141) is approved by the FDA as Vyleesi. Melanotan II is not approved anywhere. A research vial of any of the three is not the approved product.

Why is Melanotan II non-selective across melanocortin receptors?

Because its Asp-Lys lactam ring locks the His-D-Phe-Arg-Trp message motif into a conformation that every melanocortin receptor except MC2R recognizes well. A 2022 medicinal-chemistry study showed that changing only the ring linker shifts the subtype profile, which indicates the ring geometry, not the residues alone, sets selectivity.

Citations

1. Sawyer TK, Sanfilippo PJ, Hruby VJ, et al. 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
2. Al-Obeidi F, Castrucci AM, Hadley ME, Hruby VJ. Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J Med Chem. 1989;32(12):2555-2561. PMID 2555512
3. Haskell-Luevano C, Hendrata S, North C, et al. Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. J Med Chem. 1997;40(14):2133-2139. PMID 9216831
4. Tomassi S, Dimmito MP, Cai M, et al. CLIPSing Melanotan-II to Discover Multiple Functionally Selective hMCR Agonists. J Med Chem. 2022;65(5):4007-4017. PMID 35188390
5. Hedlund P. PT-141 Palatin. Curr Opin Investig Drugs. 2004;5(4):456-462. PMID 15134289
6. Mayer D, Lynch SE. Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder. Ann Pharmacother. 2020;54(7):684-690. PMID 31893927
7. Minder EI, Barman-Aksoezen J, Schneider-Yin X. Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders. Clin Pharmacokinet. 2017;56(8):815-823. PMID 28063031
8. Kim ES, Garnock-Jones KP. Afamelanotide: A Review in Erythropoietic Protoporphyria. Am J Clin Dermatol. 2016;17(2):179-185. PMID 26979527
9. Evans-Brown M, Dawson RT, Chandler M, McVeigh J. Use of melanotan I and II in the general population. BMJ. 2009;338:b566. PMID 19224885
10. Ter Laak MP, Brakkee JH, Adan RA, et al. The potent melanocortin receptor agonist melanotan-II promotes peripheral nerve regeneration and has neuroprotective properties in the rat. Eur J Pharmacol. 2003;462(1-3):179-183. PMID 12591111

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