PT-141 (Bremelanotide)

PT-141, generic name bremelanotide, is a synthetic cyclic heptapeptide analogue of α-melanocyte-stimulating hormone (α-MSH) that acts as a non-selective melanocortin receptor agonist, with its most characterised functional activity at the melanocortin-4 receptor (MC4R).

The regulatory position of this molecule is unusual and worth stating at the outset. Bremelanotide is the active ingredient of an FDA-approved prescription drug product, approved in June 2019 for a specific indication in a specific population. Research-grade material catalogued as "PT-141" is not that approved product: it has not been reviewed, manufactured, or released under the approval, and it is supplied for laboratory research use only. It is not for human or animal consumption. Full terms are set out in the research use policy.

Specifications

The formula and mass above are drawn from the PubChem record (CID 9941379) rather than from supplier literature; the formula reconciles with the stated mass on direct calculation.

Chemistry and origin

Bremelanotide belongs to the melanotan family of α-MSH analogues. Structurally it is the C-terminal free-acid form of melanotan II, differing from that parent compound by the replacement of the terminal amide with a carboxylate. The core pharmacophore common to this family — the His-D-Phe-Arg-Trp motif, constrained here inside a lactam macrocycle — is the α-MSH message sequence, and the D-phenylalanine substitution plus the ring constraint together confer resistance to proteolysis and a conformationally restricted presentation of the pharmacophore. Molinoff et al. (2003), writing in the Annals of the New York Academy of Sciences, gave the early account of the molecule's identification and rationale.

Receptor pharmacology

The melanocortin system comprises five G protein-coupled receptors, MC1R through MC5R, all Gs-coupled and signalling through adenylyl cyclase and cyclic AMP. They differ in tissue distribution: MC1R is associated with cutaneous pigmentation, MC2R with adrenal steroidogenesis, and MC3R and MC4R are expressed predominantly in the central nervous system.

Bremelanotide is an agonist across several of these receptors rather than a selective ligand, which is a defining feature of its pharmacology and the source of several of the off-target characteristics reported in the literature. Its central actions have been attributed principally to MC3R and MC4R. Pfaus et al. (2022), in a review published in CNS Spectrums, described a proposed mechanism in which activation of presynaptic MC4R on neurons of the medial preoptic area (mPOA) of the hypothalamus increases dopamine release in that region. The authors presented this as a mechanism inferred from animal studies rather than one demonstrated in humans, and the approved product's labelling states that the exact mechanism of action is unknown.

Structural biology

Zhang et al. (2021) reported high-resolution cryo-electron microscopy structures of full-length MC4R in complex with heterotrimeric Gs, solved with four different ligands bound: the endogenous peptide α-MSH, the small molecule THIQ, afamelanotide, and bremelanotide. The peptide-bound complexes were resolved at 3.0–3.1 Å, making the paper the direct structural reference for how this ligand is recognised. Its central findings concern the conserved binding mode shared by the peptidic agonists, the distinct basis of small-molecule subtype selectivity, and an activation mechanism specific to MC4R. Because MC4R shares high sequence similarity with the other melanocortin receptors, this structural work provides a direct experimental basis for examining the selectivity problem.

Published study history

The research record spans rodent behavioural neuroscience through phase 3 human trials. Models and populations are stated explicitly. All human data below pertain to formulations studied under an investigational or approved drug programme; no human data exist for research-grade material as supplied.

• Rat (ovariectomised, hormone-primed females). Pfaus et al. (2007), in The Journal of Sexual Medicine, reviewed preclinical work using a paced-mating paradigm in which the compound was reported to increase measures of solicitation without altering pacing or lordosis. The effect was described after peripheral administration and after infusion into the lateral ventricles or the mPOA, but not after infusion into the ventromedial hypothalamus — an anatomical dissociation that localised the effect. Microdialysis work described in that review was consistent with a mechanism involving dopamine terminals in the mPOA. These are rodent behavioural endpoints and do not establish an effect in humans.
• Human, early-phase. Diamond et al. (2004), in the International Journal of Impotence Research, reported a double-blind, placebo-controlled evaluation of safety, pharmacokinetics and pharmacodynamics using an intranasal formulation in healthy male volunteers and in men with mild-to-moderate erectile dysfunction.
• Human, early-phase. Rosen et al. (2004), in the same journal, reported the corresponding evaluation for a subcutaneously administered formulation in healthy male subjects and in patients with an inadequate response to sildenafil.
• Human, phase 3. Kingsberg et al. (2019), in Obstetrics and Gynecology, reported two 24-week randomised, double-blind, placebo-controlled trials (the RECONNECT programme) in premenopausal women with hypoactive sexual desire disorder. These trials formed the efficacy record submitted in the New Drug Application for the approved product.

Conflicting evidence

The phase 3 record is contested in the peer-reviewed literature. Spielmans (2021), in The Journal of Sex Research, published a re-analysis of the two RECONNECT trials drawing on the FDA New Drug Application dossier. That paper reported that 72.72% of protocol-listed outcomes went unreported in the original publication while fifteen secondary measures not listed in the protocols were reported instead; that no efficacy outcome was reported in line with CONSORT standards; that adverse-event-induced study discontinuation was substantially higher in the active arm; and that, measured by the combination of completing a trial and electing to participate in the follow-up open-label study, participants preferred placebo. The author's conclusion was critical of both the magnitude of the reported effects and the transparency of the reporting.

That re-analysis was itself disputed in print. Kingsberg et al. (2021), in a commentary in the same journal (volume 58, pages 1106–1107), rejected the re-analysis and its conclusions. Researchers evaluating this literature should read the original trial reports, the re-analysis, and the commentary together. The disagreement concerns reporting practice and the interpretation of effect sizes, not whether the trials occurred.

Regulatory status

Bremelanotide is the active ingredient in an FDA-approved prescription product, approved in June 2019 for acquired, generalised hypoactive sexual desire disorder in premenopausal women. That approval attaches to a specific manufactured product with a specific label, dispensed under prescription. It does not extend to research-grade peptide sold under the code name PT-141, which is not manufactured, tested, or released under that approval, has no approved labelling, and is not for human or animal consumption. Material supplied here is a laboratory reagent.

Identity and purity verification

Cyclic peptides present analytical problems that linear sequences do not. The most consequential is that the linear (uncyclised) precursor and the correctly cyclised product differ by only 18 Da — the mass of water — a difference easily missed on a 1025 Da molecule by a low-resolution mass measurement. Incomplete cyclisation is therefore the specific impurity worth interrogating on a certificate of analysis for this compound. A useful certificate pairs an RP-HPLC purity chromatogram with a mass-spectrometric identity confirmation of sufficient resolution to distinguish those species, together with water content and counter-ion or residual-solvent data. Third-party analysis practice is described on the lab testing page.

Handling and storage

Lyophilised material is stored at −20 °C, desiccated and protected from light. The tryptophan and histidine residues in this sequence are the ones most susceptible to oxidative and photolytic degradation, which is why light protection is not a boilerplate precaution for this particular peptide. In solution the stability window is markedly shorter than in the lyophilised state and depends on buffer composition, pH and temperature. General bench guidance is collected under peptide storage and reconstitution; solution-concentration arithmetic is handled by the peptide calculator.

Frequently asked questions

Is research-grade PT-141 the same as the approved prescription product?

No. The approved product is a specific manufactured drug product released under an FDA approval with approved labelling. Research-grade material shares the active moiety but is not that product, was not manufactured or released under that approval, and is supplied for laboratory research use only.

How should lyophilised material be stored?

At −20 °C, desiccated and protected from light, with freeze-thaw cycling minimised by aliquoting before storage. Light protection matters more for this sequence than for many peptides because of its tryptophan and histidine content.

What should a certificate of analysis show for a cyclic peptide?

An HPLC purity chromatogram, a mass-spectrometry identity confirmation with enough resolution to separate the cyclised product from its linear precursor (an 18 Da difference), water content, and counter-ion content. A bare purity percentage with no supporting trace is not verification.

Why do melanocortin agonists have off-target effects?

Because the five melanocortin receptors are closely related in sequence and most α-MSH analogues bind more than one of them. Cross-reactivity at MC1R, which is associated with cutaneous pigmentation, is the most commonly discussed consequence in the literature and is a known limitation of non-selective ligands in this class.