PT-141 (Bremelanotide): Structure and Receptors

PT-141 is the development code for bremelanotide, a synthetic cyclic heptapeptide, Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH, derived from the melanocortin hormone α-MSH. It is a nonselective agonist at the melanocortin receptors, with a published order of potency of MC1R, MC4R, MC3R, MC5R, then MC2R. It differs from Melanotan II at a single position, the C-terminus, where it carries a free carboxylic acid instead of an amide.

That one-atom difference, the receptor family it acts on, and the fact that a finished drug containing it exists are the three things worth understanding before working with the PT-141 peptide in the laboratory. This profile covers each, with identity data checked against PubChem and the FDA label.

PT-141 at a glance

The formula and weight describe the free base. Synthetic peptides are usually isolated as a salt, and the FDA label describes the acetate as carrying between one and two equivalents of acetic acid, so the mass of powder in a vial is not the same as the mass of peptide. The certificate of analysis for a lot states the counter-ion and the peptide content; our guide on how to read a peptide certificate of analysis explains where to find both.

From α-MSH to a cyclic heptapeptide

The melanocortins are peptides cut from a single precursor, pro-opiomelanocortin. The best known is α-MSH, a 13-residue peptide with the sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. Structure-activity work through the 1970s and 1980s showed that the central His-Phe-Arg-Trp segment carries most of the receptor-activating information, and that two substitutions raised potency: norleucine (Nle) for methionine at position 4, and the D-isomer of phenylalanine at position 7.

In 1989 Al-Obeidi, Castrucci, Hadley and Hruby at the University of Arizona reported a series of cyclic lactam analogues built on that core. They trimmed α-MSH to positions 4 through 10, kept Nle4 and D-Phe7, and joined the side chains of residues 5 and 10 into a lactam ring. The analogue with Asp at position 5 and Lys at position 10, which closes a 23-membered ring, was among the most potent in their skin-cell bioassays. That compound, Ac-Nle4-c[Asp5,D-Phe7,Lys10]α-MSH(4-10)-NH2, is Melanotan II.

Bremelanotide is the same seven-residue ring with the C-terminal amide replaced by a free acid. Palatin Technologies developed it under the code PT-141; a 2003 paper from the company describes it as a synthetic analogue of α-MSH with agonist activity at MC3R and MC4R. Secondary sources often call bremelanotide a metabolite of Melanotan II. The primary sources we checked establish the structural relationship (identical ring, different C-terminus) but not the metabolic one, so we state only the first. For the parent compound's own history, see the profile of Melanotan II on the Melanotan II reagent page.

Reading the sequence residue by residue

Each of the seven positions has a documented reason for being there. Numbering follows α-MSH, which is how the literature refers to these analogues.

Two practical points follow. First, because the ring is closed through side chains rather than head to tail, the molecule still has a defined N-terminus (acetylated) and C-terminus (a free acid in bremelanotide, an amide in Melanotan II). Second, the cyclization constrains the His-D-Phe-Arg-Trp core into a turn, which is the structural rationale the Arizona group gave for the jump in potency over linear analogues. For background on the amide bonds that make up the chain, see what peptides are.

The melanocortin receptor family

There are five melanocortin receptors, MC1R through MC5R. They belong to class A (rhodopsin-like) G protein-coupled receptors and are among the smallest GPCRs known, with short N- and C-terminal tails and an unusually small second extracellular loop. Four of them respond to α-MSH; MC2R responds to ACTH alone.

The canonical signal for all five is Gs coupling, adenylyl cyclase activation and a rise in intracellular cAMP. MC4R has also been reported to couple to Gi/o and Gq in some cell systems. The family is also unusual in having endogenous antagonists: agouti signaling protein and agouti-related protein (AgRP), the latter acting at MC3R and MC4R.

How bremelanotide engages the receptors

The FDA label for the approved drug describes bremelanotide as a melanocortin receptor agonist that "nonselectively activates several receptor subtypes", ranking them by potency as MC1R, MC4R, MC3R, MC5R and MC2R. The label also notes that MC1R is expressed on melanocytes and that MC4R is expressed by neurons across many areas of the central nervous system.

In practical assay terms, PT-141 is a pan-agonist with the most activity at MC1R and MC4R. That matters for experimental design:

• Receptor-specific questions need receptor-specific systems. A readout in a cell line that expresses more than one melanocortin receptor cannot be attributed to a single subtype. Heterologous expression of one receptor in a null background (HEK293 or CHO cells are common hosts) is the usual answer.
• cAMP is the natural first readout. Because all five receptors couple to Gs, cAMP accumulation or a cAMP reporter is the standard way to build a concentration-response curve.
• Antagonist controls exist. Replacing D-Phe7 in the Melanotan II scaffold with the bulkier D-2'-naphthylalanine gives SHU9119, which Hruby and colleagues showed to be an antagonist at MC3R and MC4R while remaining an agonist at MC1R and MC5R. It is a standard tool for separating subtypes.

In animal work, a 2003 paper from the developer reported increased c-Fos immunoreactivity, a marker of recent neuronal activation, in hypothalamic neurons of rats after systemic delivery. That is the kind of molecular marker the preclinical literature uses; this profile does not summarize behavioral or human findings.

Regulatory status

Bremelanotide is approved by the FDA as Vyleesi, an autoinjector product first approved in 2019 for a specific indication in premenopausal women (acquired, generalized hypoactive sexual desire disorder). The approved product is a sterile solution of bremelanotide acetate in a finished device, made under drug manufacturing controls.

A research reagent sold as PT-141 is not that product and is not a drug. Anhydrolabs supplies it as a lyophilized reagent for in-vitro research, not for human or veterinary diagnosis, treatment, or consumption. The terms are set out on the research use page.

PT-141 versus Melanotan II in the lab

The two peptides share every residue and the same ring, so they are easy to confuse and hard to tell apart by a quick look at a chromatogram.

The monoisotopic masses differ by about 0.98 Da, which is less than the spacing of the isotope envelope. On a low-resolution mass spectrometer the two can look like the same compound with a shifted isotope pattern. A 2021 forensic study of seized samples used liquid chromatography with high-resolution Orbitrap mass spectrometry and product-ion fragmentation to characterize both peptides, which is the level of analysis needed to tell them apart reliably. On reversed-phase HPLC the free acid and the amide normally separate, but only a reference standard confirms which is which. Our note on peptide purity and HPLC covers what a purity figure does and does not prove about identity.

Handling PT-141 in the laboratory

Anhydrolabs supplies PT-141 as a lyophilized powder in vacuum-sealed vials, and in 10-vial kits. General handling rules for a short, cyclic, Trp-containing peptide apply:

• Storage. Keep the sealed vial cold, dry and dark; −20 °C is the usual long-term condition for lyophilized peptides. Let the vial reach room temperature before opening so moisture does not condense on the powder. Our guide on how to store peptides covers the details.
• Stock solutions. Make a concentrated stock (for example 1 mg/mL) in water or a dilute acid, divide it into single-use aliquots and freeze them, so no aliquot is thawed twice. The step-by-step method is in how to reconstitute peptides.
• Oxidation. Norleucine removed the methionine liability of α-MSH, but Trp9 is still oxidation-sensitive. Minimize light and headspace air in stored solutions.
• Concentration checks. The single Trp residue gives the peptide useful absorbance at 280 nm, so a UV reading can check a stock against its nominal concentration, allowing for the salt and water content stated on the certificate of analysis.
• Adsorption. Hydrophobic and cationic peptides can stick to glass and some plastics at low concentration. Low-binding tubes and a carrier protein in working buffers are common precautions for dilutions below the micromolar range.