PT-141

PT-141 (bremelanotide) is a cyclic heptapeptide, Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-OH, with the formula C50H68N14O10 and a molar mass of 1025.2 g/mol. The sequence is N-terminally acetylated, incorporates norleucine and a D-phenylalanine residue, and is cyclized between the aspartate and lysine residues. It was developed as a synthetic peptide analogue of alpha-melanocyte-stimulating hormone (α-MSH) and acts as an agonist at melanocortin receptors, including the MC3R and MC4R subtypes.

PT-141 in the research literature

The melanocortin system comprises five receptors, of which MC3R and MC4R are expressed primarily in the central nervous system and are referred to as the neural melanocortin receptors. PT-141 has been characterized pharmacologically as an agonist at both. In rats, the peptide was reported to activate hypothalamic neurons, measured as increased c-Fos immunoreactivity.

Structural work has examined how the peptide engages its receptor. A 2021 cryo-electron microscopy study reported high-resolution structures of full-length MC4R in complex with the heterotrimeric Gs protein, bound in turn to the endogenous ligand α-MSH, to PT-141, to a related peptide agonist and to the small-molecule ligand THIQ. Together with accompanying pharmacological assays, the structures revealed a conserved binding mode among peptidic agonists and a distinct activation mechanism for MC4R.