PT-141 (Bremelanotide)

PT-141 (Bremelanotide, Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH) is a synthetic cyclic heptapeptide melanocortin receptor agonist with preferential activity at MC4R and MC3R over MC1R. Structurally derived from MT-2 (Melanotan II) by C-terminal modification, PT-141 received FDA approval in June 2019 as Vyleesi for hypoactive sexual desire disorder (HSDD) in premenopausal women — the only FDA-approved melanocortin receptor agonist and the first centrally acting pharmacotherapy for female sexual dysfunction.

The cyclic lactam bridge (Asp2-Lys7) in PT-141 is identical to that of MT-2, providing the conformational constraint that positions the His-D-Phe-Arg-Trp pharmacophore for high-affinity MCR binding. The C-terminal modification that distinguishes PT-141 from MT-2 shifts the receptor balance toward central MCR subtypes (MC4R, MC3R) over peripheral MC1R, and the modification improves CNS penetration relative to MT-2. This CNS penetration makes PT-141 the preferred melanocortin tool for research examining central neural circuits — particularly hypothalamic and limbic system MC4R pathways.

MC4R is expressed in hypothalamic paraventricular nucleus (PVN), arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, brainstem raphe nuclei, and limbic system areas including hippocampus and amygdala. MC4R activation in these central circuits drives downstream effects through autonomic nervous system outflow pathways — sympathetic projections from hypothalamus to spinal cord intermediolateral cell column and from there to peripheral organs. The mechanism of PT-141 action is entirely distinct from PDE5 inhibitors (sildenafil, tadalafil) that act peripherally on vascular smooth muscle cGMP: PT-141 activates the CNS desire and arousal circuitry, while PDE5 inhibitors facilitate peripheral physiological responses to arousal that has already been generated.

Published Phase 3 RECONNECT trial data provides an extensive pharmacological reference: subcutaneous Tmax approximately 1 hour; plasma half-life approximately 2.7 hours; bioavailability approximately 70-80% subcutaneous; no significant CYP enzyme drug-drug interactions; confirmed CNS penetration through central pharmacological effects at doses producing defined plasma concentrations. This published clinical dataset contextualises laboratory research — in vitro incubation times of 1-4 hours bracket the clinical Tmax-to-half-life window, and receptor concentrations in functional assays can be referenced to published plasma exposure ranges.

Biased agonism research: PT-141 has been characterised for functional selectivity (biased agonism) at MC4R — preferentially engaging G-protein signalling pathways over beta-arrestin recruitment under some assay conditions. Quantifying bias factors requires parallel measurement of cAMP accumulation (G-protein, Gs pathway) and beta-arrestin recruitment (arrestin pathway) in the same receptor preparation using matched assay conditions. The Black-Leff operational model applied to these parallel datasets generates a transduction ratio (tau/KA) for each pathway, and the ratio of ratios (versus a balanced reference agonist) quantifies the bias factor.

Research applications: MC4R and MC3R cAMP functional assays in receptor-expressing CHO or HEK293 cells; beta-arrestin recruitment assays (BRET with beta-arrestin2-Venus fusion); MC4R versus MC1R selectivity profiling alongside MT-1; hypothalamic neuron electrophysiology in PVN slice preparations; and energy homeostasis research examining MC4R-mediated POMC/AgRP circuit modulation.

MW: 1025.18 g/mol. CAS: 189691-06-3. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.

For MC4R biased agonism research comparing PT-141 with MT-2: use CHO cells stably co-expressing human MC4R with either a Gs-coupled cAMP biosensor (CAMYEL-BRET or GloSensor-22F) or beta-arrestin2-Venus for BRET-based arrestin recruitment. Run parallel assays measuring cAMP (Gs) and beta-arrestin (arrestin) at matched receptor occupancy concentrations for both PT-141 and MT-2. Calculate transduction ratios (log(Emax/EC50)) for each pathway and each compound; the difference in transduction ratios (log bias factor) quantifies functional selectivity. Include NDP-MSH (Nle4,D-Phe7-alpha-MSH) as a balanced reference agonist (bias factor = 0 by definition). This systematic biased agonism characterisation demonstrates the pharmacological distinction between PT-141 (CNS-focused, potentially biased) and MT-2 (pan-MCR, reference compound). MW: 1025.18 g/mol. CAS: 189691-06-3. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.