PT-141research overview.

Overview

PT-141 is the development code for bremelanotide, a synthetic cyclic heptapeptide in the melanocortin family. Hadley and Dorr, whose University of Arizona group worked on the earlier melanotan peptides, describe PT-141 as an analogue of melanotan II taken into clinical development by Palatin Technologies ¹.

Melanocortins are peptides cut from the precursor pro-opiomelanocortin. They include α-⁠melanocyte-stimulating hormone (α-⁠MSH) and ACTH, and act at five melanocortin receptor subtypes, MC1R to MC5R. Molinoff et al. (2003) described PT-141 as an agonist at melanocortin receptors including MC3R and MC4R, both expressed mainly in the central nervous system ².

Bremelanotide is the active ingredient of a prescription medicine approved by the US FDA in 2019 ⁶. OzPept’s PT-141 is a research chemical, not a medicine, and is not for human use.

Structure and chemistry

Sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH. Molecular formula C50H68N14O10, molecular weight 1025.2 g/mol, CAS 189691-06-3.

Three design features set it apart from native α-⁠MSH, a linear 13-residue peptide. First, it keeps only the central His-Phe-Arg-Trp sequence, the core motif shared by melanocortin peptides. Second, phenylalanine is replaced by its D-isomer, D-Phe, a substitution widely used in melanocortin analogues. Third, the ring is closed by a lactam (amide) bridge between the side-chain carboxyl of Asp and the side-chain amine of Lys. Hadley and Dorr describe analogues built this way as more potent, longer acting and more resistant to enzymes than the native hormone ¹.

The N-terminus is acetylated norleucine (Nle), a methionine isostere that cannot be oxidised at sulfur, used in place of the methionine at position 4 of α-⁠MSH. PT-141 differs from melanotan II at the other end: melanotan II has a C-terminal amide, while PT-141 ends in a free carboxylic acid, shown as -OH in the sequence.

Mechanisms investigated

Research on PT-141 has concentrated on melanocortin receptors in the brain, particularly MC4R, and on behavioural and physiological endpoints that follow from activating them.

• Receptor activity. Molinoff et al. (2003) described PT-141 as an agonist at MC3R and MC4R, among other melanocortin receptors ². The 2019 approval review by Dhillon and Keam describes high affinity for MC4R ⁶.
• Central activation. In rats, systemic administration was followed by increased c-Fos immunoreactivity in hypothalamic neurons, a marker of recent neuronal activation ².
• Behavioural paradigm. Pfaus et al. (2004) scored separate components of female rat behaviour in a standard paradigm ⁴.
• Pharmacokinetics. An early placebo-controlled study measured pharmacokinetics in healthy men ³.
• Phase 3 programme. Kingsberg et al. (2019) reported two identically designed randomised, placebo-controlled phase 3 trials in premenopausal women, with co-primary endpoints measured by validated questionnaires ⁵.

Research areas

• Melanocortin receptor pharmacology at MC3R and MC4R (in vitro and animal) ^2,6
• Hypothalamic c-Fos mapping in rats (animal) ²
• Female rat behavioural paradigms (animal) ⁴
• Physiological response models in rats and non-human primates (animal) ²
• Placebo-controlled pharmacokinetic studies in men (human) ³
• Two phase 3 randomised controlled trials with questionnaire endpoints (human) ⁵
• Origins in melanotan II and melanocortin analogue design (review) ¹

Limits of the evidence

Unlike most compounds in this library, PT-141 has a large human trial programme behind it: 1,267 participants were randomised across the two phase 3 trials ⁵. Those trials studied a defined medicine in a defined population under regulatory conditions. Their findings describe that product in that setting, not research-grade material.

Many of the early preclinical and clinical papers share authors, including Molinoff, Shadiack and Diamond, so independent replication is narrower than the number of papers suggests ^2,3,4.

Animal behavioural endpoints are indirect and depend on how each behaviour is defined and scored. PT-141 is not selective for a single melanocortin receptor, and these receptors are also found outside the brain, so interpreting any experiment means considering activity across more than one receptor subtype.

OzPept’s PT-141 is a research chemical, not a medicine, and is not for human use.

Key studies

1. 2003Animal

   MC3R and MC4R agonism, hypothalamic c-Fos in rats ²

2. 2004Human

   Placebo-controlled pharmacokinetic study in men ³

3. 2004Animal

   Female rat behavioural components ⁴

4. 2006Review

   Melanocortin analogues from melanotan to PT-141 ¹

5. 2019Human

   Two randomised phase 3 trials ⁵

6. 2019Review

   FDA approval and development history ⁶

Questions

References

1. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-930. Source
2. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. 2003;994:96-102. Source
3. Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res. 2004;16(1):51-59. Source
4. Pfaus JG, Shadiack A, Van Soest T, Tse M, Molinoff P. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc Natl Acad Sci U S A. 2004. doi:10.1073/pnas.0400491101. Source
5. 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. Source
6. Dhillon S, Keam SJ. Bremelanotide: first approval. Drugs. 2019;79(14):1599-1606. Source