— Research note —
PT-141 (Bremelanotide)
Cyclic heptapeptide melanocortin receptor agonist investigated in sexual response research and approved for hypoactive sexual desire disorder.
PT-141, also known as bremelanotide, is a cyclic heptapeptide melanocortin receptor agonist developed by Palatin Technologies. The molecule was derived from earlier research on Melanotan II, an alpha-MSH analog originally synthesized at the University of Arizona, by enzymatic cleavage to remove the C-terminal amide and yield a metabolite with distinct receptor binding properties. Bremelanotide received regulatory approval in 2019 in the United States for treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women, making it one of the few peptides to reach pharmaceutical approval in this therapeutic area.
The pharmacology of bremelanotide is distinguished by activity at melanocortin-4 receptor (MC4R), with lower affinity at MC3R and MC1R. Central engagement of MC4R in hypothalamic circuits regulating sexual response, including medial preoptic area and paraventricular nucleus, has been proposed as the mechanism underlying the observed effects on sexual desire in research populations. The compound's central rather than peripheral mechanism distinguishes it from PDE5 inhibitors and supports administration on an as-needed basis.
In clinical research, the RECONNECT phase 3 trials in women with HSDD demonstrated improvements in patient-reported measures of sexual desire and reductions in distress associated with low desire. Phase 1 and phase 2 research had previously characterized effects on erectile response in male research populations, although development for that indication was discontinued. Academic interest in the compound extends to melanocortin receptor pharmacology, central sexual response circuits, and the structure-activity relationships of cyclic peptide melanocortin agonists.
PT-141 is supplied here for laboratory research use only and is not intended for human consumption. Its primary research applications include melanocortin receptor pharmacology, central nervous system pharmacology of sexual response, and comparative studies with related melanocortin analogs.
Mechanism
Bremelanotide engages multiple melanocortin receptor subtypes with a preference for MC4R, the principal receptor mediating central regulation of energy balance, sexual response, and certain behavioral effects. MC4R is a class A G-protein coupled receptor expressed prominently in hypothalamus, brainstem, and limbic structures, and is coupled to Gas with downstream cAMP elevation.
The proposed mechanism of action in sexual response involves engagement of MC4R in central nuclei including the paraventricular nucleus and medial preoptic area, with downstream effects on oxytocinergic, dopaminergic, and other neurotransmitter systems implicated in sexual desire. The compound does not act on peripheral vascular targets that mediate the effects of PDE5 inhibitors, supporting a centrally-mediated rather than peripherally-mediated mechanism. Bremelanotide also retains affinity at MC1R, the receptor responsible for pigmentation effects of alpha-MSH, and at MC3R, with potential contributions to observed effects on appetite and energy balance in some preclinical studies.
Research history
The Palatin Technologies program that produced bremelanotide built on earlier University of Arizona research by Hadley and colleagues characterizing structure-activity relationships of alpha-MSH analogs, including Melanotan II. Bremelanotide was identified as a metabolite of Melanotan II generated by hydrolysis of the C-terminal amide, with distinct receptor binding properties favoring MC4R over MC1R.
Initial clinical research in the 2000s examined intranasal and subcutaneous formulations for male erectile response. While early phase 2 studies reported activity, development was complicated by blood pressure observations leading to reformulation. Subsequent research focused on female sexual dysfunction, with the RECONNECT phase 3 program in HSDD reporting positive results in 2016 and supporting regulatory approval in 2019.
Academic research has continued to examine the central nervous system actions of bremelanotide and related melanocortin agonists. The compound has been used as a probe for MC4R-mediated behavioral effects in preclinical models and as a reference compound in structure-activity studies of cyclic peptide melanocortin analogs. Related melanocortin pharmacology, including the broader characterization of MC4R signaling in obesity and behavior, continues to be informed by research with this compound and related analogs.
References
- Kingsberg SA, et al. 2019. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. PMID: 30801473
- Diamond LE, et al. 2004. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide. J Sex Med. PMID: 16422989
- Molinoff PB, et al. 2003. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. PMID: 12724147
- Pfaus J, et al. 2007. The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder. CNS Spectr.
- Wessells H, et al. 2000. Effect of an alpha-melanocyte stimulating hormone analogue on penile erection and sexual desire in men with organic erectile dysfunction. Urology. PMID: 10792358
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Information presented in third-person scientific context. Research use only. Not medical advice; not for human consumption.