PT-141 (Bremelanotide) - Melanocortin Receptor Agonist

PT-141 (Bremelanotide) for Research: Complete Scientific Overview

PT-141 (Bremelanotide) is a synthetic cyclic heptapeptide developed through extensive structure-activity relationship studies of melanocortin peptides at the University of Arizona. It represents a refined analog of Melanotan II, specifically designed to enhance selectivity for central melanocortin receptors (MC3R and MC4R) while significantly minimizing activity at peripheral MC1R (pigmentation). This selectivity profile makes PT-141 a uniquely valuable tool for dissecting the specific physiological roles of MC3R and MC4R without the confounding effects of pigmentation seen with other melanocortin agonists. The peptide received FDA approval for clinical use in 2019, highlighting its well-characterized pharmacology.

Mechanism of Action

PT-141 exerts its effects through selective activation of melanocortin receptors with a distinct pharmacological profile:

• MC4R Activation (Primary): High-affinity agonist at the melanocortin 4 receptor (MC4R), which is abundantly expressed in the central nervous system, particularly in the hypothalamus, brainstem, and spinal cord. MC4R activation modulates neural circuits involved in sexual behavior, erectile function, and energy homeostasis. The MC4R is a G-protein coupled receptor that signals primarily through Gs proteins, leading to adenylate cyclase activation and increased intracellular cAMP.
• MC3R Activation (Secondary): Moderate affinity for MC3R, which is also expressed in the CNS and plays roles in energy homeostasis, feeding behavior, and reproductive function. The combined MC3R/MC4R activation profile contributes to the peptide's overall pharmacological effects.
• Reduced MC1R Activity: Compared to Melanotan II, PT-141 shows significantly lower affinity for MC1R (approximately 10-fold reduced), minimizing effects on melanogenesis and pigmentation. This selectivity is achieved through specific amino acid substitutions that alter the peptide's conformational preference away from the MC1R binding interface.
• Central Nervous System Action: As a centrally acting melanocortin agonist, PT-141 modulates hypothalamic and brainstem pathways involved in sexual function. The primary site of action is believed to be the paraventricular nucleus (PVN) of the hypothalamus, where MC4R activation facilitates neuronal nitric oxide synthase (nNOS) activation and downstream erectile signaling.
• Cyclic Structure Advantage: The lactam bridge between Lysine and Aspartic acid residues creates a constrained cyclic conformation that enhances receptor binding affinity, improves metabolic stability, and increases resistance to proteolytic degradation compared to linear peptides.
• cAMP-PKA Pathway: All melanocortin receptors are G-protein coupled receptors (GPCRs) that primarily signal through Gs proteins, leading to adenylate cyclase activation, increased intracellular cAMP, and PKA-mediated phosphorylation of downstream targets including CREB and other transcription factors.

Structural Characteristics

PT-141 (Bremelanotide) is a cyclic heptapeptide with the core sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH. Key structural features include:

• Cyclic Lactam Bridge: A covalent amide bond between the side chains of Aspartic acid and Lysine creates a stable cyclic structure that locks the peptide into a bioactive conformation optimized for MC4R binding.
• D-Amino Acid: The presence of D-Phenylalanine (D-Phe) at position 7 confers resistance to proteolytic degradation and enhances receptor binding affinity compared to L-Phe-containing analogs.
• C-Terminal Free Acid: Unlike Melanotan II (which has a C-terminal amide), PT-141 has a free C-terminal carboxylic acid, which contributes to its distinct receptor selectivity profile and reduced MC1R activity.
• Norleucine Substitution: Nle (norleucine) at the N-terminus replaces methionine, eliminating oxidation potential and improving shelf stability.
• His-D-Phe-Arg-Trp Core: This tetrapeptide core sequence is essential for melanocortin receptor recognition and activation, with the D-Phe residue being critical for high-affinity binding.

Research Applications

• Sexual Function Research: Investigating the neural circuits and molecular mechanisms underlying sexual behavior, erectile function, and libido in both male and female research models. The MC4R pathway is a key focus of these studies.
• MC3R/MC4R Receptor Pharmacology: Characterizing receptor binding kinetics, signaling pathways, and structure-activity relationships of central melanocortin receptors using a selective agonist.
• Melanocortin System and Behavior: Studying the role of melanocortin receptors in various behaviors including feeding, anxiety, social interaction, and reward processing.
• Hypothalamic-Pituitary-Gonadal Axis: Investigating the interactions between melanocortin signaling and the HPG axis, including effects on gonadotropin-releasing hormone (GnRH) secretion and reproductive hormone regulation.
• Central Nervous System Signaling: Understanding the neural pathways and neurotransmitter systems (including dopamine, oxytocin, and nitric oxide) that mediate the behavioral effects of melanocortin receptor activation.
• Selective Melanocortin Agonist Development: Using PT-141 as a reference compound for developing novel melanocortin receptor ligands with improved selectivity or pharmacokinetic properties.
• Comparative Melanocortin Pharmacology: Comparing the pharmacological profiles of PT-141, Melanotan I, and Melanotan II to understand the structural determinants of receptor selectivity and functional activity.
• Energy Homeostasis Research: Investigating the role of MC4R in appetite regulation, metabolic rate, and body weight control, though PT-141 is less commonly used for this purpose compared to other melanocortin agonists.

Comparison: PT-141 vs. Melanotan II

• Melanotan II (MT-2): Broad melanocortin agonist with high affinity for MC1R, MC3R, and MC4R. Significant pigmentation effects due to MC1R activation. C-terminal amide enhances stability but reduces MC4R selectivity.
• PT-141 (Bremelanotide): Selective MC3R/MC4R agonist with approximately 10-fold reduced MC1R affinity. Minimal pigmentation effects, making it more specific for central melanocortin research. C-terminal free acid contributes to distinct receptor selectivity profile.

Chemical Information

CAS Number: 189691-06-3
Research Code: PT-141, Bremelanotide
Molecular Formula: C50H68N14O10
Molecular Weight: 1025.2 g/mol
Sequence: Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH
Receptor Targets: MC3R, MC4R (primary); MC1R (minimal)
Structure: Cyclic lactam (c[Asp-His-D-Phe-Arg-Trp-Lys])
Purity: >99% (HPLC)
Form: Lyophilized powder
Storage: -20°C (lyophilized), 4°C (reconstituted)
Stability: Stable at -20°C for 24 months; reconstituted solution stable at 4°C for 30 days

Reconstitution and Handling Protocols

For optimal stability and research validity, PT-141 should be reconstituted with sterile bacteriostatic water or sterile saline (0.9% NaCl). Allow the lyophilized powder to dissolve completely without vigorous shaking to maintain peptide integrity. Gently swirl the vial until the solution is clear and free of particulates. Once reconstituted, the solution should be stored at 4°C and used within 30 days. Avoid repeated freeze-thaw cycles to preserve peptide structure and biological activity. For long-term storage, keep the lyophilized powder at -20°C away from light and moisture. Do not vortex or vigorously shake the reconstituted solution, as this may cause aggregation and reduce melanocortin receptor binding activity.

Quality Assurance

PeptideVanta's PT-141 undergoes rigorous quality control including HPLC purity analysis (>99%), ESI-mass spectrometry for molecular weight confirmation, endotoxin testing (<1.0 EU/mg), sterility testing, and residual solvent analysis. Each batch is accompanied by a Certificate of Analysis (COA) with complete testing results.