PT-141 (Bremelanotide): Melanocortin Receptor Research and Regulatory History

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.

PT-141, known by its nonproprietary name bremelanotide, is a cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone that binds the melanocortin receptor family and exists as an approved drug product under the name Vyleesi. This article covers the lactam-bridged structure and its one-atom difference from Melanotan II, the 1989 to 1997 medicinal chemistry that produced it, the melanocortin receptor family and the 2020 to 2021 MC4R structures, the regulatory history, and what a research certificate must show.

What PT-141 is: a cyclic lactam heptapeptide

Bremelanotide is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH, with the formula C₅₀H₆₈N₁₄O₁₀, a molecular weight of 1025.2, PubChem CID 9941379 and CAS 189691-06-3. The approved product is the acetate salt. The structure has four features worth decoding. The N-terminus is acetylated. Position 1 is norleucine (Nle), a straight-chain isostere of methionine that cannot be oxidized to a sulfoxide. Position 4 is D-phenylalanine rather than the natural L-form. And the ring is not a disulfide but a lactam: the side-chain carboxyl of Asp² is condensed with the side-chain amine of Lys⁷, closing a 23-membered ring that holds His-D-Phe-Arg-Trp, the four-residue melanocortin core sequence, in a fixed turn.

The molecule's closest relative is Melanotan II, Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂. The two differ only at the C-terminus: Melanotan II is a carboxamide and bremelanotide is the free carboxylic acid. The development literature describes bremelanotide as the des-amide form of Melanotan II. That one-atom difference changes the mass by a single dalton (1024.2 versus 1025.2), removes a hydrogen-bond donor, and adds a negative charge at neutral pH. The three-way comparison sets the two cyclic analogs beside the linear afamelanotide; the point for this article is analytical, and it is covered in the certificate section below.

Where it came from: the Arizona cyclic lactam program

The compound descends directly from structure-activity work on alpha-MSH, the 13-residue pituitary peptide Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂, at the University of Arizona. Earlier studies had shown that substituting Nle for Met⁴ and D-Phe for Phe⁷ produced the superpotent linear analog NDP-MSH. Al-Obeidi, Castrucci, Hadley and Hruby then reported in the Journal of Medicinal Chemistry in 1989 a series of cyclic lactam analogs of the alpha-MSH(4-10) fragment, designed from molecular dynamics, in which a side-chain lactam between an acidic residue at position 5 and a basic residue at position 10 replaced the flexible backbone with a ring. In frog and lizard skin bioassays, the 23-membered-ring analog with Asp⁵ and Lys¹⁰ was roughly 100-fold more potent than alpha-MSH in the lizard assay and showed prolonged residual activity; ring sizes of 20, 21 or 22 atoms lost both properties. That Asp-Lys 23-membered compound is Melanotan II.

Two later papers from the same circle defined the ring's receptor pharmacology once the human receptors had been cloned. Hruby and colleagues showed in 1995 that placing a bulky aromatic residue at position 7 of the same template converted the agonist into a potent antagonist at specific melanocortin receptors, producing the tool compound SHU9119. Haskell-Luevano and colleagues reported in 1997 a systematic examination of stereochemistry at positions 5, 7 and 9 of the template on human MC1R, MC3R, MC4R and MC5R expressed in cells, finding that D-Phe⁷ was essential for high-affinity binding at MC3R and MC5R, that the chirality of Asp⁵ mattered for the lactam geometry, and that MC1R and MC4R showed similar structure-activity trends while MC3R and MC5R formed a second pair. Hadley and Hruby's 1998 review in Pharmaceutical Biotechnology recounts how Melanotan I (afamelanotide) and Melanotan II were selected from this series, a history the Melanotan overview covers in more detail.

The melanocortin receptor family

Melanocortin receptors are class A G protein-coupled receptors that couple through G_s to adenylyl cyclase and cyclic AMP. Mountjoy, Robbins, Mortrud and Cone cloned the first two members, MC1R and MC2R, and reported them in Science in 1992; Gantz and colleagues cloned MC4R and reported it in the Journal of Biological Chemistry in 1993. Five subtypes are now recognized, and they differ in their endogenous ligands, their distribution and their response to the same synthetic analogs, which is why receptor selectivity dominates the melanocortin literature.

The 2019 Drugs "First Approval" review by Dhillon and Keam describes bremelanotide as a synthetic alpha-MSH analog with high affinity for MC4R; the cyclic lactam scaffold is not subtype-selective, and the 1997 cell-binding data show measurable affinity at MC1R, MC3R and MC5R as well. The endogenous antagonist of MC1R and MC4R is agouti-related protein, and the family is the same one targeted by the small alpha-MSH fragment covered in the KPV overview. The GPCR primer covers the shared receptor mechanics.

MC4R structures, 2020 to 2021: how the ring binds

Four structural papers published within eighteen months turned the melanocortin pharmacophore from an inference into a picture. Yu and colleagues reported the first MC4R crystal structure in Science in 2020, bound to the antagonist SHU9119, and identified a calcium ion complexed by residues from both the receptor and the peptide ligand; extracellular calcium raised the affinity and potency of alpha-MSH at MC4R by 37-fold and 600-fold respectively in their assays. They also described MC4R as structurally closer to lipid-binding GPCRs than to other peptide receptors. Israeli and colleagues reported an active-state cryo-EM structure in Science in 2021 that described the activation mechanism, and Heyder and colleagues reported active MC4R-G_s complexes with NDP-alpha-MSH and setmelanotide in Cell Research the same year.

The paper most relevant to PT-141 is Zhang and colleagues' 2021 Cell Research report of four MC4R-G_s structures, with alpha-MSH, afamelanotide, bremelanotide and the small molecule THIQ. Across the three peptides the authors found a conserved binding mode in which the His-D-Phe-Arg-Trp core inserts into the orthosteric pocket, with the D-Phe and Trp side chains occupying hydrophobic subpockets and the Arg engaging acidic receptor residues, while the lactam ring of bremelanotide holds that core in the receptor-bound turn. The structural work also places the calcium site at the ligand-receptor interface, which explains why calcium concentration matters in any melanocortin binding or cAMP assay. For a research lab the message is that assays with cyclic melanocortin analogs are sensitive to buffer calcium and to which receptor subtype the cell line expresses, and that results across papers are comparable only when both are matched.

Regulatory history and why a research vial is not Vyleesi

Bremelanotide was developed by Palatin Technologies, licensed to AMAG Pharmaceuticals for North America, and approved by the FDA as Vyleesi on June 21, 2019, under NDA 210557, for the indication described in its prescribing information; the application is now held by Cosette Pharmaceuticals. The approved article is bremelanotide acetate in a finished, sterile, single-use presentation. Of the three cyclic and linear melanocortin analogs in the research catalog, bremelanotide and afamelanotide (approved by the FDA as Scenesse in 2019) are approved drugs, and Melanotan II has never been submitted for approval anywhere, a distinction the FDA status table records.

A research-grade PT-141 vial is not Vyleesi. It is a laboratory reagent: synthesized and lyophilized in the USA, characterized by an independent US laboratory, and supplied under a research-use-only attestation, with no approval of any kind. For PT-141 10 mg the lot-matched certificate reports identity by mass spectrometry against the expected mass of 1025.2, purity by HPLC, net peptide content, endotoxin, sterility and heavy metals, with the label mass referring to the lyophilized fill. The PT-141 liquid spray 10 mg (10 mL) is documented by total labeled mass per bottle and its buffer composition.

Reading a PT-141 certificate: the one-dalton problem

The analytical difficulty specific to this compound is distinguishing it from Melanotan II. The two share every residue, the same lactam ring and the same acetyl cap, and differ by one dalton of mass and one unit of charge. A low-resolution mass spectrum that reports a nominal mass of "1024" or "1025" with a tolerance of one dalton cannot separate them, so a certificate for PT-141 should show either a high-resolution monoisotopic mass (1024.52 for bremelanotide, 1023.54 for Melanotan II) or an HPLC retention time compared against a reference standard of the free acid, which typically elutes earlier than the amide on reverse phase because of its additional negative charge. The LC-MS identity article explains how to read that resolution and the charge-state pattern.

Three other lines deserve attention. The Trp⁵ indole is the residue sensitive to light and oxidation, and oxidized tryptophan appears as a +16 dalton species and a late shoulder on HPLC. The Nle¹ substitution means there is no methionine sulfoxide pathway, which is one reason the cyclic analogs are more stable than alpha-MSH in solution. And the lactam ring is chemically robust compared with a disulfide: it does not scramble or form dimers under mildly oxidizing conditions, so the aggregate peaks typical of oxytocin-type peptides are not expected. As with every short peptide, the dry lyophilizate kept cold, dark and dry is the stable form, and the storage and stability guide covers the general practice.

Frequently Asked Questions

Is PT-141 the same as bremelanotide?

Yes. PT-141 was Palatin Technologies' development code; bremelanotide is the International Nonproprietary Name; Vyleesi is the US brand of the approved bremelanotide acetate drug product. All three refer to Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH.

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

One atom at the C-terminus. Melanotan II ends in a carboxamide (-NH₂) and bremelanotide ends in a free carboxylic acid (-OH), making bremelanotide the des-amide form. Their masses differ by one dalton, which is why a PT-141 certificate needs high-resolution mass spectrometry or a reference-standard HPLC comparison to confirm which compound is in the vial.

Is PT-141 approved by the FDA?

Bremelanotide acetate was approved by the FDA as Vyleesi on June 21, 2019 (NDA 210557). That approval covers the finished drug product only. A research-grade PT-141 vial or liquid spray is not Vyleesi and is not an approved drug.

Which receptors does PT-141 bind?

Bremelanotide binds the melanocortin receptor family, with the approval review describing its highest affinity at MC4R. The cyclic lactam scaffold it shares with Melanotan II also shows measurable affinity at MC1R, MC3R and MC5R in cell-binding studies, and a 2021 cryo-EM structure shows its His-D-Phe-Arg-Trp core occupying the MC4R orthosteric pocket.

Citations

1. 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;32:2555-2561. PMID 2555512
2. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257:1248-1251. PMID 1325670
3. Gantz I, Miwa H, Konda Y, et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem. 1993;268:15174-15179. PMID 8392067
4. Hruby VJ, Lu D, Sharma SD, et al. Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5,D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem. 1995;38:3454-3461. PMID 7658432
5. Haskell-Luevano C, Nikiforovich G, Sharma SD, et al. Biological and conformational examination of stereochemical modifications using the template melanotropin peptide, Ac-Nle-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2, on human melanocortin receptors. J Med Chem. 1997;40:1738-1748. PMID 9171884
6. Hadley ME, Hruby VJ, Jiang J, et al. Discovery and development of novel melanogenic drugs. Melanotan-I and -II. Pharm Biotechnol. 1998;11:575-595. PMID 9760697
7. Dhillon S, Keam SJ. Bremelanotide: First Approval. Drugs. 2019;79:1599-1606. PMID 31429064
8. Yu J, Gimenez LE, Hernandez CC, et al. Determination of the melanocortin-4 receptor structure identifies Ca²⁺ as a cofactor for ligand binding. Science. 2020;368:428-433. PMID 32327598
9. Israeli H, Degtjarik O, Fierro F, et al. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling. Science. 2021;372:808-814. PMID 33858992
10. Heyder NA, Kleinau G, Speck D, et al. Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-alpha-MSH and setmelanotide. Cell Res. 2021;31:1176-1189. PMID 34561620
11. Zhang H, Chen LN, Yang D, et al. Structural insights into ligand recognition and activation of the melanocortin-4 receptor. Cell Res. 2021;31:1163-1175. PMID 34433901
12. US FDA. Drugs@FDA: NDA 210557, Vyleesi (bremelanotide acetate), approved June 21, 2019. Drugs@FDA
13. PubChem. Bremelanotide, CID 9941379. PubChem

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