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Melanotan II (MT-II) Research Standard
Melanotan II (CAS 121062-08-6), also indexed as MT-II, is the cyclic heptapeptide Ac-Nle-cyclo(Asp-His6-D-Phe7-Arg8-Trp-Lys)-NH2, supplied as a 10 mg lyophilized powder in a 3 mL vial. It is described in the medicinal-chemistry literature as a pan-agonist at the melanocortin receptors, and it is the scaffold from which subtype-selective analogues have repeatedly been built.[1]
Mechanism of Action & Research Context
The molecular targets are the melanocortin receptors, five class A GPCRs signalling through Gs and cyclic AMP.
The parent scaffold for selective design. Cyclic peptides derived from MT-II, incorporating sterically constrained hydrophobic residues at positions 6 and 8 and a D-4,4′-biphenylalanine at position 7, produced potent MC5R-selective agonists — one reaching IC50 0.95 nM and EC50 0.99 nM with greater than 5000-fold selectivity over the other subtypes. Starting from a pan-agonist and engineering selectivity into it is a repeatable strategy in this family.[1]
The lactam bridge does the work. The Asp-Lys side-chain bridge closes the peptide into a macrocycle, pre-organising the His-Phe-Arg-Trp message sequence into its bioactive orientation rather than leaving it flexible as in a linear analogue.
Related to PT-141 by one change. Bremelanotide is the C-terminal acid analogue of this scaffold rather than the amide. Holding the two side by side isolates what that single terminal modification does to subtype preference.
Five receptors, not one. The melanocortin family comprises MC1R–MC5R, class A GPCRs coupling to Gs, adenylyl cyclase and cyclic AMP. cAMP accumulation is the standard functional readout, and real-time luminescent cAMP reporters in receptor-expressing HEK293 lines are an established platform for quantifying it.[5]
The message sequence engages subtypes differently. Systematic truncation of NDP-α-MSH established that the conserved His-Phe-Arg-Trp core does not bind and stimulate each subtype in the same fashion, overturning the earlier assumption of a shared binding mode.[2]
Residue chemistry drives selectivity. In α-MSH/γ-MSH hybrid series, increasing hydrophobicity and substituting bulkier aromatic residues at positions 6 and 8 separates MC1R-preferring from MC3R-preferring analogues.[3]
Research Applications
Primary fields of in vitro and preclinical laboratory investigation include:
Receptor binding panels across MC1R–MC5R with a pan-agonist anchor.[4]
cAMP functional assays in CHO or HEK293 lines expressing human receptors.[1,5]
Structure-activity relationship work engineering subtype selectivity into the cyclic scaffold.[1,3]
Conformational constraint studies comparing cyclic against linear analogues such as NDP-α-MSH.[2]
Analytical Documentation
Purity and identity vary by manufacturing lot. Kimera Chems does not publish a single fixed purity figure for this item; refer to the batch-specific Certificate of Analysis (COA) issued for the lot received, which reflects third-party analytical testing for that lot.
References
- Bednarek MA, MacNeil T, Tang R, et al. Potent and selective agonists of human melanocortin receptor 5: cyclic analogues of alpha-melanocyte-stimulating hormone. J Med Chem. 2007;50(10):2520–2526. doi:10.1021/jm0614275
- Haskell-Luevano C, Hendrata S, North C, et al. Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. J Med Chem. 1997;40(14):2133–2139. doi:10.1021/jm960840h
- Cai M, Mayorov AV, Cabello C, et al. Novel 3D pharmacophore of alpha-MSH/gamma-MSH hybrids leads to selective human MC1R and MC3R analogues. J Med Chem. 2005;48(6):1839–1848. doi:10.1021/jm049579s
- Schiöth HB, Muceniece R, Wikberg JE. Characterization of the binding of MSH-B, HB-228, GHRP-6 and 153N-6 to the human melanocortin receptor subtypes. Neuropeptides. 1997;31(6):565–571. doi:10.1016/s0143-4179(97)90002-0
- Pantel J, Williams SY, Mi D, et al. Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay. Eur J Pharmacol. 2011;660(1):139–147. doi:10.1016/j.ejphar.2011.01.031
