PT-141

PT-141 is the development code for bremelanotide, a seven-residue cyclic peptide modelled on alpha-melanocyte-stimulating hormone (alpha-MSH) that binds melanocortin receptors. This listing is a sealed vial holding 10 mg of freeze-dried bremelanotide, acetylated at the N-terminus and ending in a free carboxylic acid. Research on the compound covers how its ring was designed, which receptors it reaches in the brain, animal studies of hypothalamic activation, and two phase 3 trials whose design is summarised below.

Bremelanotide or melanotan II: reading the structure

Bremelanotide and melanotan II share one ring: an acetylated norleucine followed by Asp-His-D-Phe-Arg-Trp-Lys, closed by a lactam bond between the aspartate and lysine side chains. They differ only at the C-terminus. Melanotan II ends in an amide, bremelanotide in a free acid. The certificate writes the structure in one-letter code as Ac-Nle-cyclo[D-H-[D-Phe]-R-W-K]-OH, where the first D stands for aspartate and the only D-amino acid is the bracketed phenylalanine. Formula C50H68N14O10, theoretical mass 1025.2 Da.

Melanotan II has a theoretical mass of 1024.2 Da, so the two sit about one dalton apart, and the LC-MS identity result on the certificate is the number to read against 1025.2. From that mass, 10 mg is about 9.8 µmol, a little less once the certificate's water content is allowed for. The melanotan 1 vs melanotan 2 guide places both in the wider family of alpha-MSH analogues.

What the research covers

Where the ring came from

Bremelanotide descends from structure-based work on alpha-MSH in the 1980s. Al-Obeidi and colleagues used molecular dynamics to design cyclic fragments of the hormone, each closed by a lactam bridge between two side chains, and tested seven of them in frog and lizard skin bioassays¹. Ring size mattered. In the lizard assay the analogues bridged from aspartate to lysine were 90 to 100 times as potent as alpha-MSH, while the glutamate-bridged versions reached 6 to 9¹. The seven-residue Asp-to-Lys peptide in that series has the sequence later known as melanotan II, and a 2006 review by Hadley and Dorr described PT-141 as a newer analogue of melanotan II developed by Palatin Technologies². The link to sexual function came by chance: Hadley wrote that the effects of melanotan II in this area were discovered accidentally while the peptide was being studied for skin pigmentation³.

Receptors and where they sit

The melanocortin system is made up of peptides cut from the proopiomelanocortin precursor, five melanocortin receptors, two endogenous antagonists and two ancillary proteins⁴. Gantz and Fong's 2003 review listed pigmentation, inflammation, energy homeostasis and sexual function as the roles that pharmacological and genetic studies had confirmed for it⁴. Molinoff and colleagues described PT-141 as an agonist at melanocortin receptors including MC3R and MC4R, the two expressed mainly in the central nervous system⁵. Because bremelanotide is not confined to one receptor, an effect seen with it cannot be assigned to a single receptor without further tools. The binding order across all five receptors is set out in the PT-141 and bremelanotide guide.

Animal and early human studies

In the same paper, PT-141 given systemically to rats increased c-Fos immunoreactivity, a marker of recently active neurons, in the hypothalamus⁵. A tracing experiment pointed to that region as well: hypothalamic neurons picked up a pseudorabies virus tracer placed in the rat corpus cavernosum⁵. The authors also reported erectile responses in rats and nonhuman primates, and summarised early studies in healthy men and in men with erectile dysfunction that measured erectile activity⁵.

Phase 3 trials

The largest human data set in these references is the RECONNECT programme: two identical phase 3, randomised, double-blind, placebo-controlled, multicentre trials in premenopausal women with hypoactive sexual desire disorder, each lasting 24 weeks⁶. Of 1,267 women randomised, 1,247 formed the safety population and 1,202 the efficacy population; 96.6% were enrolled at US sites, and the mean age was 39⁶. The co-primary endpoints were the change from baseline in the desire domain of the Female Sexual Function Index and in item 13 of the Female Sexual Distress Scale-Desire/Arousal/Orgasm⁶. The measured differences, the adverse events and the criticism the trials have drawn are covered in the guide.

What is not established

The central site of action rests on c-Fos mapping and tracer work in rats⁵, which shows where the peptide acts in rodents rather than how it produces trial endpoints in people. Hadley is an author on three of the six papers cited here, and the 2003 and 2006 reviews predate the phase 3 results². None of the studies used SCALE Performance material or tested bremelanotide stored and handled the way a research vial is.

Frequently asked questions

References

1. Al-Obeidi F, Castrucci AM, Hadley ME, et al. Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J Med Chem. 1989;32(12):2555-61. DOI · PubMed
2. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-30. DOI · PubMed
3. Hadley ME. Discovery that a melanocortin regulates sexual functions in male and female humans. Peptides. 2005;26(10):1687-9. DOI · PubMed
4. Gantz I, Fong TM. The melanocortin system. Am J Physiol Endocrinol Metab. 2003;284(3):E468-74. DOI · PubMed
5. Molinoff PB, Shadiack AM, Earle D, et al. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. 2003;994:96-102. DOI · PubMed
6. Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. 2019;134(5):899-908. DOI · PubMed