PT-141 (Bremelanotide)

What PT-141 is

PT-141, known by its international non-proprietary name bremelanotide, is a synthetic cyclic heptapeptide and an agonist at the melanocortin family of G-protein-coupled receptors. Its structure is written Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH: an N-terminal acetyl group, a norleucine residue, and a ring of six residues closed by a lactam bridge between the side-chain carboxylate of aspartate and the side-chain amine of lysine. The His-D-Phe-Arg-Trp core is the pharmacophore that every melanocortin agonist peptide shares with the native hormone α-melanocyte-stimulating hormone (α-MSH), and the D-phenylalanine at position 7 is the substitution that converts a short-lived natural sequence into a protease-resistant, high-affinity analogue [1, 2].

The compound's origin is unusual. It is a metabolite of Melanotan II (MT-II), the cyclic lactam analogue developed in the laboratory of Victor Hruby and Mac Hadley at the University of Arizona in the 1980s as a tanning agent [1]. MT-II carries a C-terminal carboxamide; bremelanotide is the corresponding carboxylic acid, the product of hydrolysis of that amide. During the clinical development of MT-II, Wessells and colleagues reported in 1998 that it produced penile erections in a double-blind crossover study of men with psychogenic erectile dysfunction, an observation unconnected to pigmentation that pointed to a central melanocortin mechanism [3]. Palatin Technologies, which had licensed the Arizona work, identified the deamidated metabolite, found it retained the receptor activity of the parent, and took it forward as PT-141 [2]. The reference identifiers for the free peptide are in the table; the values on any batch certificate should agree with them within the precision of the method used.

Research-grade PT-141 is supplied as a white to off-white lyophilised powder, normally as the acetate salt. The two compounds differ by a single mass unit, so identity by mass spectrometry needs a method that resolves them, and a certificate should state which has been supplied.

How the literature describes its mechanism

The melanocortin system comprises five receptors, MC1R to MC5R, all of which respond to peptides derived from pro-opiomelanocortin. MC1R governs pigmentation in melanocytes; MC2R is the adrenocorticotropin receptor; MC3R and MC4R are expressed principally in the central nervous system, where MC4R in particular is a well-characterised regulator of energy balance and autonomic output; and MC5R is involved in exocrine function. Bremelanotide binds across the family rather than to one member. The regulatory summaries describe it as a non-selective agonist at MC1R, MC3R, MC4R and MC5R, with the highest affinity and functional activity at MC4R and MC1R [4, 5]. The affinity for MC1R is the structural basis of the pigmentary effects noted in the trials, discussed below; the affinity for MC4R is the basis of the central effects for which it was developed.

The central mechanism is what distinguishes PT-141 pharmacologically from the phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, and the distinction is the single most important thing to understand about the compound. PDE5 inhibitors act peripherally, on vascular smooth muscle, by preventing the breakdown of cyclic GMP downstream of nitric oxide; they do nothing in the absence of a nitric oxide signal. Bremelanotide does not act on the vasculature of the target tissue at all. The preclinical account from Palatin, set out by Molinoff and colleagues in 2003, places its site of action in the hypothalamus, with the medial preoptic area and paraventricular nucleus as the regions implicated by lesion and microinjection studies of melanocortin agonists [2]. The compound's effects in animal models are abolished by MC4R antagonists and are observed after central administration at doses far below those required peripherally, which is the standard evidence for a central locus [2, 6].

The most cited behavioural study is that of Pfaus and colleagues in 2004. Working with ovariectomised, hormone-primed female rats, they reported that bremelanotide selectively increased solicitation behaviours directed at a male without altering lordosis, and that the effect was blocked by a melanocortin antagonist [6]. The result bears on mechanism rather than on any clinical claim: it showed that the compound altered appetitive rather than consummatory behaviour, through melanocortin receptors in the brain.

Human imaging work has since been added. Thurston and colleagues at Imperial College London, in a randomised, double-blind, placebo-controlled crossover study published in 2022, used functional MRI in 31 premenopausal women after bremelanotide or placebo and reported altered activity in the cerebellum, supplementary motor area and secondary somatosensory cortex and a change in amygdala–insula connectivity, which they interpreted as evidence for a central mode of action consistent with the animal work [7]. The point for a reader outside the field is that the compound's pharmacodynamic signature in humans is a change in brain network activity, not in peripheral haemodynamics.

A second consequence of the mechanism, bearing directly on the clinical history, is cardiovascular. MC4R agonism increases sympathetic outflow and raises blood pressure in animals and humans, a class property independent of the behavioural effect [4, 5, 8]. This is what sank the first clinical formulation.

For an in-vitro programme, the relevant readouts are those established for melanocortin ligands generally: competitive binding against labelled NDP-α-MSH at recombinant MC1R, MC3R, MC4R and MC5R, and cAMP accumulation in cells expressing each receptor. Bremelanotide is a useful reference agonist in such assays because its receptor profile is published.

The research record

PT-141 is one of the few compounds in the catalogue that progressed through full clinical development to a marketing authorisation, and that history is set out here as pharmacology. Nothing in it is a basis for using the research material in any living system.

The intranasal programme. Palatin's first clinical formulation was an intranasal spray. Diamond and colleagues reported in 2004 a double-blind, placebo-controlled study of intranasal PT-141 in healthy men and in men with mild to moderate erectile dysfunction, with pharmacokinetic sampling and penile plethysmography, and found a pharmacodynamic response with a time course consistent with the plasma profile [9]. A companion study by Rosen and colleagues in the same year examined subcutaneous administration in healthy men and in men who had responded inadequately to sildenafil [10]. A 2006 study by Diamond and colleagues extended the intranasal formulation to premenopausal women with sexual arousal disorder, using a laboratory paradigm with subjective and physiological measures [11]. In 2008, Safarinejad and Hosseini published a randomised controlled study of intranasal bremelanotide in men who had failed sildenafil; the Journal of Urology issued an expression of concern about that paper in January 2023, and it should be read with that in mind [12].

The intranasal programme was stopped in 2007 and 2008 after the US Food and Drug Administration raised concerns about increases in blood pressure: intranasal dosing produced a rapid rise in plasma concentration and a corresponding pressor response [4, 5]. Palatin reformulated the compound for subcutaneous administration, which gives a slower, lower peak, and restarted development in women.

Phase 2 and the ethanol study. Clayton and colleagues reported in 2016 a randomised, placebo-controlled, dose-finding trial in premenopausal women, comparing three subcutaneous dose levels with placebo over 12 weeks, which selected the dose carried into phase 3 [13]. Because the pressor effect was the known liability, Palatin also ran a phase 1 study of bremelanotide co-administered with ethanol in healthy men and women; it found that ethanol attenuated rather than potentiated the blood-pressure increase, with more orthostatic symptoms in the combination arm [8].

Phase 3: RECONNECT. The two pivotal trials, RECONNECT studies 301 and 302, were identical in design: randomised, double-blind, placebo-controlled, 24-week studies in premenopausal women with hypoactive sexual desire disorder, with the Female Sexual Function Index desire domain and the Female Sexual Distress Scale item 13 as co-primary endpoints. Kingsberg and colleagues reported the efficacy results in Obstetrics & Gynecology in November 2019: 1,267 women were randomised, and both studies met both co-primary endpoints, with statistically significant improvements in desire and reductions in distress relative to placebo [14]. The effect sizes were modest, and the paper reports them as such.

The adverse-event profile from the same trials is the part of the record of most interest to a pharmacologist, because every item on it maps onto a known melanocortin receptor. Nausea was the most common event, reported by about 40% of women on bremelanotide against about 1% on placebo, and was the main reason for discontinuation; flushing was reported by about 20% and headache by about 11% [14]. Nausea and flushing are consistent with central MC4R and peripheral MC1R activity respectively. Focal hyperpigmentation, darkening of the skin on the face, gums or breasts, occurred in about 1% of participants and was more frequent in women with darker skin; this is the MC1R effect, the same mechanism by which the parent compound MT-II produces tanning [4, 14]. Blood pressure rose transiently after each dose, by a mean of roughly 6 mmHg systolic and 3 mmHg diastolic, peaking within a few hours and returning to baseline within about 12 hours, with a corresponding small fall in heart rate [4, 5, 14]. The pressor effect was judged manageable with the subcutaneous formulation but is the reason the licensed product carries restrictions for people with cardiovascular disease and uncontrolled hypertension [4, 5].

Simon and colleagues reported the 52-week open-label extension in the same issue of the journal, in which women who completed the core studies continued for a further year. The safety profile was unchanged over the longer exposure, with no new signals, and the proportion with focal hyperpigmentation remained low [15].

Approval. The FDA approved bremelanotide, under the brand name Vyleesi, on 21 June 2019 for the treatment of acquired, generalised hypoactive sexual desire disorder in premenopausal women. It was the first melanocortin agonist to be licensed for any indication and the second drug of any kind to be licensed for that condition. Dhillon and Keam's "First Approval" summary in Drugs and the review by Mayer and Lynch in the Annals of Pharmacotherapy set out the approval package [4, 5]. The human pharmacokinetics are straightforward: after subcutaneous administration peak plasma concentration is reached in about an hour, the elimination half-life is about 2.7 hours, metabolism is by hydrolysis of the amide bonds, and elimination is mostly renal [4]. A 2022 review by Edinoff and colleagues surveys the whole record for a general readership [16].

The compound and the drug are different things. The licensed product is a sterile solution in a single-use device, manufactured under good manufacturing practice and dispensed on prescription in the United States. The research material described here is a lyophilised peptide of defined purity for laboratory assays. They share a molecule and nothing else, and this page describes the clinical history because a researcher should know it, not because the research material is an alternative to the medicine.

Regulatory status in the United Kingdom

PT-141 is not licensed as a medicine in the United Kingdom. It has no marketing authorisation from the Medicines and Healthcare products Regulatory Agency, and no monograph in the British Pharmacopoeia or the European Pharmacopoeia. Nor is it licensed in the European Union: Palatin licensed European rights to Gedeon Richter in 2014, the agreement was terminated in September 2015 before the phase 3 trials reported, and no marketing authorisation application was taken through the European Medicines Agency's centralised procedure. The statement sometimes seen in commercial literature that bremelanotide was "rejected" in Europe is therefore inaccurate; the position is that it was never assessed. BuyUK Peptides supplies PT-141 as a research chemical for in-vitro laboratory use under the Terms of Sale. It is not for human or veterinary administration. Purchasers must be 18 or over and are responsible for ensuring their use of the material complies with the laws and institutional rules that apply to them. Our guide to the UK rules on research compounds sets this out in more detail.

The anti-doping position differs from that of most compounds on this site. The World Anti-Doping Agency's S0 category covers substances with no current approval by any governmental regulatory health authority for human therapeutic use; because bremelanotide holds an FDA approval, S0 does not apply to it, and it is not named in any of the specific classes S1 to S9 of the Prohibited List. On our reading it is not a prohibited substance, which distinguishes it from BPC-157 and from the unapproved MT-II. We state this as a reading rather than a ruling, and any researcher subject to anti-doping rules should confirm the current position with UK Anti-Doping or Global DRO.

Handling, storage and stability

PT-141 is supplied lyophilised in a glass vial with a rubber stopper and an aluminium flip-off crimp. A cyclic, lactam-bridged heptapeptide with no cysteine and no lipid chain, it is chemically robust compared with linear peptides of similar size, and the D-phenylalanine and norleucine substitutions were introduced precisely to confer resistance to proteolysis [1, 2]. Two residues nevertheless need attention: tryptophan, which is susceptible to oxidation and photodegradation, and histidine, which is also oxidation-prone. Protection from light is therefore more important for this compound than for a peptide such as BPC-157.

Sealed vial. Store at 2–8 °C for routine use and at −20 °C or below for storage beyond a few months. Protect from light at all times. Avoid repeated freeze–thaw cycles. Allow a refrigerated vial to reach room temperature before opening, so that moisture does not condense onto the cake.

Reconstitution. For in-vitro work the compound is reconstituted in sterile water, bacteriostatic water or an assay buffer. With the N-terminus acetylated and the lysine side chain tied up in the lactam, the free peptide's charge at neutral pH comes from arginine and, in part, histidine, so it is a cationic peptide: the acetate salt dissolves readily in water and in dilute acid and is less soluble at high pH. Add the solvent down the side of the vial and swirl gently; the cake should clear within seconds, and sonication is not needed. The reconstitution calculator gives the volume to add for a target concentration.

Reconstituted solution. Keep at 2–8 °C and protect from light. The published half-life figures concern elimination in vivo and say nothing about chemical stability in clean aqueous solution, which for a cyclic peptide of this kind is expected to be good. The conservative practice is to use a research solution within 28 days, to aliquot into single-use volumes and freeze at −20 °C where the buffer permits, and to discard any solution that becomes cloudy or discoloured; a yellow tinge is a sign of tryptophan oxidation.

Solubility and adsorption. PT-141 acetate is soluble in water, in phosphate-buffered saline and in DMSO. Like other cationic, tryptophan-containing peptides it adsorbs to untreated polystyrene, so stock solutions are better held in low-binding polypropylene, and where sterile filtration is required a low-protein-binding PVDF or PES membrane at 0.22 µm is preferable. Carrier protein in the assay buffer limits losses at nanomolar working concentrations.

What a sound certificate for PT-141 looks like

Every batch we release carries an independent certificate of analysis, and the figures from it are transcribed on the product page and in the certificate register. For PT-141 a certificate should contain the following, and a reader should be able to check each item against this monograph.

Purity by RP-HPLC. Reversed-phase HPLC on a C18 column with UV detection at 214 or 220 nm reports purity as the area of the main peak as a percentage of all integrated peaks; the tryptophan residue also gives a usable signal at 280 nm. A good batch shows a single dominant peak with purity of 98% or above. The impurities to look for in a cyclic lactam peptide are the uncyclised linear precursor, which has the same mass plus 18 Da, and the C-terminal amide (that is, MT-II itself), which can arise if the synthesis was run on an amide resin or if the two products have been confused in the supply chain.

Identity by LC-MS. Electrospray mass spectrometry confirms that the main peak has the expected mass. For PT-141 the average molecular weight is 1025.2 Da and the monoisotopic mass is approximately 1024.5 Da; the peptide usually appears as the doubly charged [M+2H]2+ ion at about 513.3 and the singly charged [M+H]+ at about 1025.5, and the observed mass should agree with the theoretical value to within about 0.5 Da. Because MT-II is one mass unit lighter, a nominal-mass instrument cannot distinguish the two with confidence; the certificate should report an accurate-mass measurement or rely on chromatographic separation, which is good on most C18 methods because the free acid elutes earlier than the amide.

Net peptide content. Lyophilised peptides contain bound water and counter-ions, usually acetate or trifluoroacetate, so the mass of powder in the vial is more than the mass of peptide. Net peptide content, where reported, expresses the fraction that is actual peptide, and it matters for binding assays, where a 20% error in nominal concentration shifts an apparent affinity by the same amount.

Endotoxin. Where the batch has been tested, a limulus amoebocyte lysate (LAL) result is reported in endotoxin units per milligram.

Our guide to reading a certificate of analysis goes through a complete report line by line.

Related compounds

PT-141 is most naturally read alongside Melanotan II, from which it is derived and differs only at the C-terminus; MT-II has full tanning activity through MC1R and remains unapproved anywhere. Neither should be confused with Melanotan I (afamelanotide), the linear analogue licensed in the UK and EU as Scenesse for erythropoietic protoporphyria. GHK-Cu sits in the same catalogue class for reasons of chemistry rather than pharmacology: a short, metal-binding peptide that handles similarly at the bench, with a mechanism, through copper delivery and gene expression, unrelated to the melanocortin system.

Frequently asked questions

Is PT-141 the same as bremelanotide? Yes. PT-141 was Palatin's development code; bremelanotide is the international non-proprietary name; Vyleesi is the brand name of the licensed medicine in the United States [4].

How does it differ from Melanotan II? By a single functional group. MT-II has a C-terminal carboxamide; PT-141 is the corresponding carboxylic acid, formed by hydrolysis of that amide, and it was first identified as a metabolite of MT-II [2]. The two are one mass unit apart and need a resolving method to distinguish.

Which receptors does it bind? It is a non-selective agonist across MC1R, MC3R, MC4R and MC5R with the highest activity at MC4R and MC1R [4, 5]. It does not act on MC2R.

Is it a vasodilator like sildenafil? No. Its site of action is the hypothalamus, not vascular smooth muscle, and if anything its cardiovascular effect is a transient rise in blood pressure rather than a fall [2, 4, 8].

Is it licensed in the UK? No. It holds an FDA approval in the United States but has no MHRA or EMA authorisation, and the European licence was terminated before any application was made. The material sold here is a research chemical for in-vitro use only.

How long does a sealed vial last? Cyclic peptides of this kind are stable for years at −20 °C and for many months at 2–8 °C provided they are kept dark. The batch certificate reports the test date; the storage guidance on this page applies from receipt.

References

1. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921–930. doi:10.1016/j.peptides.2005.01.029.
2. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Annals of the New York Academy of Sciences. 2003;994:96–102. doi:10.1111/j.1749-6632.2003.tb03167.x. PMID 12851303.
3. Wessells H, Fuciarelli K, Hansen J, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. Journal of Urology. 1998;160(2):389–393. doi:10.1016/S0022-5347(01)62903-3.
4. Dhillon S, Keam SJ. Bremelanotide: first approval. Drugs. 2019;79(14):1599–1606. doi:10.1007/s40265-019-01187-w.
5. Mayer D, Lynch SE. Bremelanotide: new drug approved for treating hypoactive sexual desire disorder. Annals of Pharmacotherapy. 2020;54(7):684–690. doi:10.1177/1060028019899152.
6. 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. Proceedings of the National Academy of Sciences. 2004;101(27):10201–10204. doi:10.1073/pnas.0400491101.
7. Thurston L, Hunjan T, Mills EG, et al. Melanocortin 4 receptor agonism enhances sexual brain processing in women with hypoactive sexual desire disorder. Journal of Clinical Investigation. 2022;132(19):e152341. doi:10.1172/JCI152341.
8. Clayton AH, Lucas J, DeRogatis LR, Jordan R. Phase I randomized placebo-controlled, double-blind study of the safety and tolerability of bremelanotide coadministered with ethanol in healthy male and female participants. Clinical Therapeutics. 2017;39(3):514–526.e14. doi:10.1016/j.clinthera.2017.01.018.
9. 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. International Journal of Impotence Research. 2004;16(1):51–59. doi:10.1038/sj.ijir.3901139.
10. Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. International Journal of Impotence Research. 2004;16(2):135–142. doi:10.1038/sj.ijir.3901200.
11. Diamond LE, Earle DC, Heiman JR, Rosen RC, Perelman MA, Harning R. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. Journal of Sexual Medicine. 2006;3(4):628–638. doi:10.1111/j.1743-6109.2006.00268.x.
12. Safarinejad MR, Hosseini SY. Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study. Journal of Urology. 2008;179(3):1066–1071. doi:10.1016/j.juro.2007.10.063. Expression of concern issued by the journal, January 2023.
13. Clayton AH, Althof SE, Kingsberg S, et al. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Women's Health. 2016;12(3):325–337. doi:10.2217/whe-2016-0018.
14. Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstetrics & Gynecology. 2019;134(5):899–908. doi:10.1097/AOG.0000000000003500.
15. Simon JA, Kingsberg SA, Portman D, et al. Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder. Obstetrics & Gynecology. 2019;134(5):909–917. doi:10.1097/AOG.0000000000003514.
16. Edinoff AN, Sanders NM, Lewis KB, et al. Bremelanotide for treatment of female hypoactive sexual desire. Neurology International. 2022;14(1):75–88. doi:10.3390/neurolint14010006.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.