Melanotan-2: Non-Selective Cyclic Melanocortin Agonist — Structure and Multi-Receptor Pharmacology
Development
Melanotan-2 (MT-2) was developed at the University of Arizona by the same Hruby-Hadley research group that created Melanotan-1, but with a fundamentally different structural approach. Rather than creating a linear analog of α-MSH, the team designed a cyclic lactam peptide constrained into a β-turn conformation that mimics the bioactive conformation of the His-Phe-Arg-Trp pharmacophore. This cyclization strategy yielded a compound with a distinct melanocortin receptor binding profile compared to its linear predecessor.
Chemical Structure
Melanotan-2 is a synthetic cyclic heptapeptide with the sequence Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂ (MW ~1,024 Da). Structural features include:
- Lactam bridge: A covalent amide bond between the Asp and Lys side chains creates a 23-membered macrocyclic ring, constraining the peptide into a type II' β-turn
- Nle (norleucine): N-terminal modification, same rationale as in MT-1
- D-Phe: D-configuration at the phenylalanine position enhances affinity and proteolytic stability
- Reduced molecular weight: At ~1,024 Da, MT-2 is significantly smaller than the 13-residue MT-1 (~1,647 Da)
The cyclic constraint is the defining structural feature, locking the pharmacophore into a conformation that interacts with multiple melanocortin receptor subtypes.
Receptor Pharmacology
Unlike MC1R-preferring Melanotan-1, MT-2 is a non-selective melanocortin receptor agonist with significant binding affinity at MC1R, MC3R, MC4R, and MC5R. The receptor binding profile has been characterized by radioligand displacement and functional cAMP assays:
- MC1R: melanogenesis signaling in melanocytes
- MC3R: expressed in hypothalamus and immune cells; roles in energy homeostasis and inflammatory signaling
- MC4R: hypothalamic receptor involved in appetite regulation, autonomic function, and neuroendocrine signaling
- MC5R: expressed in exocrine glands; involved in sebaceous lipid secretion regulation
Key Published Studies
- Hruby VJ et al. (1995) — Detailed structure-activity relationship analysis of cyclic melanotropin analogs.
- Hadley ME et al. (1999) — Comprehensive review of melanotropic peptide research and MC receptor pharmacology.
- Wikberg JE et al. (2000) — Melanocortin receptor classification and pharmacological characterization.
Future Research Directions
MT-2's non-selective profile makes it valuable as a broad melanocortin system probe, but current research is focused on developing receptor subtype-selective analogs to dissect the contributions of individual MC receptor subtypes. The cyclic lactam scaffold has become a template for extensive SAR studies in melanocortin receptor medicinal chemistry.
Available at Crush Research: Melanotan-2 10mg. View Certificates of Analysis.
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