What Has Published Research Reported About PT-141?

What is PT-141?

PT-141 is the code name used in the early research literature (source 8) for the synthetic peptide now named bremelanotide (source 1), which acts on melanocortin receptors. The U.S. prescribing information describes the substance as a synthetic, cyclic heptapeptide with an acetylated amino terminus and a free acid at the carboxyl terminus, and gives its sequence as Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH (source 1). The same document gives the molecular formula as C50H68N14O10 and the molecular weight of the free base as 1025.2 (source 1). The approved product is bremelanotide acetate, a salt, so the mass of a weighed sample includes the counterion (source 1).

This Steadfast Research Group profile summarizes what the primary literature reported about PT-141, from the peptide chemistry that preceded it to the receptor and animal studies published in the early 2000s. It is written for researchers reading that record and reports published observations only. Related background on the field is in the overview of research peptides.

How did PT-141 emerge from alpha-MSH research?

PT-141 belongs to a line of work that began with modifying the natural hormone alpha-melanocyte-stimulating hormone (alpha-MSH). In 1980, Sawyer, Hruby, Hadley and colleagues reported a version carrying norleucine at position 4 and D-phenylalanine at position 7 (source 2). The authors described it as about 26 times as potent as alpha-MSH in an adenylate cyclase assay, resistant to breakdown by serum enzymes, and prolonged in its biological activity, and they proposed it as a molecular probe for melanotropin receptors (source 2). The sequence in the current label contains the same two kinds of substitution, norleucine and D-phenylalanine (source 1).

A 1989 paper from Al-Obeidi, Castrucci, Hadley and Hruby extended the approach to ring-closed analogs. Its title described potent and prolonged-acting cyclic lactam analogs of alpha-melanotropin designed on the basis of molecular dynamics (source 3). A lactam is an amide bond formed between side chains, and the label sequence for PT-141 is written as a ring closed between its aspartic acid and lysine residues (source 1). In 2006, Hadley and Dorr published a review that traced the historical milestones, clinical studies and commercialization of the melanocortin peptide analogs, and it named PT-141 among its subjects (source 4).

What are melanocortin receptors and which ones does PT-141 engage?

Cone reviewed the melanocortin system in 2006, including his laboratory’s role in cloning the receptors. The review described the system as influencing pigmentation, adrenal steroid production, energy balance, sodium excretion, erectile responses and exocrine secretion (source 5). A fourth melanocortin receptor was cloned and characterized by Gantz and colleagues in 1993 (source 6), and the prescribing information refers to five subtypes, MC1R through MC5R (source 1).

PT-141 was reported to act at more than one subtype. The 2003 paper by Molinoff and colleagues at Palatin Technologies described it as an alpha-MSH analog acting mainly on MC3R and MC4R, receptors concentrated in the central nervous system (source 8). A 2007 review by King and colleagues described PT-141 as a nonspecific agonist, concluded that MC4R appears to be the main effector of melanocortin-induced erection, and called the role of MC3R less clear (source 7). The prescribing information describes bremelanotide as a nonselective agonist, lists the subtypes in the order MC1R, MC4R, MC3R, MC5R and MC2R, and states that MC1R is expressed on melanocytes and that MC4R neurons are present in many areas of the central nervous system (source 1).

What did animal studies report?

Molinoff and colleagues summarized early preclinical findings in Annals of the New York Academy of Sciences in 2003 (source 8). The paper reported that PT-141 produced penile erections in rats and in nonhuman primates, and that systemic administration to rats increased c-Fos immunoreactivity in hypothalamic neurons, a marker of neuronal activation (source 8). Because the authors worked at the company developing the compound, this early summary was not an independent characterization.

In 2004, Pfaus, Shadiack, Van Soest, Tse and Molinoff reported a behavioral study in female rats in PNAS (source 9). PT-141 selectively stimulated solicitation, a precopulatory behavior, without affecting lordosis, pacing or other sexual behaviors. The authors reported that it did not cause generalized motor activation and did not alter the perception of sexual reward, and they concluded that central melanocortin systems appear to be important for female sexual desire (source 9). Its title described the facilitation as selective (source 9).

Work on the receptor itself came from a different group. Van der Ploeg and colleagues, writing in PNAS in 2002, combined genetic, pharmacological and anatomical approaches to study the role of MC4R in sexual function (source 10). The authors reported that a highly selective nonpeptide MC4R agonist augmented erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type mice but not in Mc4r-null mice, and they pointed to spinal cord erectile centers and penile sensory nerve endings as possible sites of action (source 10). That experiment used a nonpeptide compound, not PT-141, so it speaks to the receptor and not to the peptide.

What does the regulatory record say?

A prescription product containing bremelanotide acetate, marketed as Vyleesi, carries initial U.S. approval dated 2019 under NDA 210557 (source 1). Its prescribing information is a regulatory document for that medicine and is not a research protocol. The label’s pharmacology section described the compound as a melanocortin receptor agonist and stated that the mechanism by which the product acts in its labeled use is unknown (source 1). That statement is a useful reminder that receptor pharmacology and the downstream biology were not fully connected even after approval. Research material supplied by Steadfast Research Group is labeled for laboratory use only and is a separate matter from that regulated product.

What terms recur in the PT-141 literature?

Melanocortin receptor

One of a family of G protein-coupled receptors activated by alpha-MSH and related peptides, discussed as MC1R through MC5R (sources 5 and 6).

Agonist

A compound that activates its receptor. PT-141 was described as a nonspecific melanocortin receptor agonist (source 7).

Norleucine (Nle)

A non-natural amino acid at position 4 in the early alpha-MSH analogs and in the sequence of PT-141 (sources 1 and 2).

Lactam bridge

The side-chain amide bond that closes the peptide ring, drawn between aspartic acid and lysine in the label sequence (sources 1 and 3).

c-Fos

A protein whose immunoreactivity marks recently activated neurons, measured in rat hypothalamus after PT-141 (source 8).

Solicitation

A precopulatory behavior of the female rat, the behavior selectively increased in the 2004 study (source 9).

What remains unresolved in the PT-141 literature?

Several points were left open. The King review noted conflicting evidence about which central receptor, MC3R or MC4R, mediates melanocortin-induced erection, while concluding that MC4R appeared to be the main effector (source 7). Sources also differ in emphasis on receptor selectivity: the early company paper stressed MC3R and MC4R (source 8), and the label lists MC1R first among the subtypes it ranks (source 1). Binding constants for the full receptor panel were not available in the abstracts reviewed here, so this profile does not print affinity numbers.

The two principal animal papers, the 2003 summary and the 2004 behavioral study, were written by authors from the same company that developed the compound (sources 8 and 9), and the knockout work used a different molecule (source 10). Independent replication with PT-141 itself was not identified in the sources reviewed.

How can a laboratory confirm the identity of PT-141?

Identity can be checked against the formula and sequence in the label: C50H68N14O10, with a free-base molecular weight of 1025.2 (source 1). Because the peptide is supplied as an acetate salt, a Certificate of Analysis should state the form tested and any peptide-content correction. The carboxyl-terminal acid also matters. Calculated from standard atomic masses, a terminal acid differs from a terminal amide by roughly 1 dalton, which a mass spectrometer can resolve, so a related amide-terminated analog is distinguishable by its measured mass. This is a calculated difference, not a figure from a cited paper.

Mass spectrometry confirms identity and HPLC reports purity. The guide to verifying research material quality covers counterion and water content in more detail.