MT-2 (Melanotan II)

MT-2 (Melanotan II, Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH) is a synthetic cyclic heptapeptide pan-melanocortin receptor agonist activating MC1R, MC3R, MC4R, and MC5R with high affinity. The cyclic lactam bridge connecting Asp2 and Lys7 pre-organises the central His-D-Phe-Arg-Trp pharmacophore in its receptor-binding conformation, dramatically increasing binding affinity across all MCR subtypes relative to the linear alpha-MSH parent through conformational constraint.

MT-2 was developed by Hruby and colleagues at the University of Arizona (Journal of Medicinal Chemistry, 1987) as the first high-affinity cyclic melanocortin agonist — representing a landmark in peptide medicinal chemistry demonstrating that cyclisation-induced conformational constraint could dramatically improve receptor binding affinity. MT-2 served as the structural template from which PT-141 (Bremelanotide) was subsequently derived, and its cyclic Asp-Lys lactam bridge has become a design principle in peptide drug development extending beyond melanocortin pharmacology.

The mechanistic basis for MT-2's pan-MCR activity versus MT-1's MC1R selectivity reveals fundamental principles of MCR pharmacology. Both compounds share the His-Phe-Arg-Trp core pharmacophore. MT-1's linear 13 amino acid structure adopts flexible solution conformations, and the geometry most easily adopted naturally favours MC1R binding. MT-2's cyclic constraint fixes the His-D-Phe-Arg-Trp geometry in a conformation that fits MC1R, MC3R, MC4R, and MC5R binding pockets with high affinity. The D-Phe (versus L-Phe in alpha-MSH) further stabilises the receptor-binding turn conformation. This conformational insight has driven design of subtype-selective cyclic analogues with different ring geometries favouring individual MCR subtypes.

MC4R activation by MT-2 connects to hypothalamic energy homeostasis research. MC4R in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus is the primary melanocortin receptor regulating appetite and energy expenditure. POMC neurons releasing alpha-MSH activate MC4R to produce anorexigenic effects; AgRP neurons release AgRP (an MC4R inverse agonist) to drive appetite. MT-2's high MC4R activity provides a pharmacological tool for activating this system independently of endogenous AgRP/POMC balance, enabling research into MC4R signalling in hypothalamic slice preparations, primary hypothalamic neuron cultures, and immortalised hypothalamic cell lines.

MC3R activation connects MT-2 to adipose tissue energy sensing, macrophage inflammatory regulation, and thermogenic brown adipose tissue biology — research dimensions not accessible with MC1R-selective MT-1. MC5R activation connects to exocrine gland biology and immune cell function.

The structural relationship between MT-2 and PT-141 is direct: PT-141 was derived by C-terminal modification of MT-2, maintaining the identical cyclic lactam ring. The resulting pharmacological shift toward CNS MC4R/MC3R (PT-141) versus peripheral pan-MCR coverage (MT-2) reveals the contribution of the C-terminal modification to receptor distribution access and selectivity.

For pan-MCR comparative research: prepare MT-1, MT-2, and PT-141 at matched molar concentrations (account for MW differences: MT-1 1646.87, MT-2 1024.18, PT-141 1025.18 g/mol). Run cAMP assays in parallel wells of cells expressing MC1R, MC3R, MC4R, and MC5R individually. Normalise to maximal response of alpha-NDP-MSH (full agonist reference). This 3 compounds x 4 receptors matrix directly maps the selectivity profile of each compound across the full melanocortin receptor family and identifies research contexts where each compound is most appropriate. Receptor antagonists for selectivity confirmation: agouti protein (MC1R), SHU9119 (MC3R/MC4R), HS-024 (MC4R-selective). MW: 1024.18 g/mol. CAS: 121062-08-6. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.