Potent and selective MC-4 receptor agonists based on a novel disulfide scaffold

Extensive structure–activity relationship studies utilizing a β-MSH-derived cyclic nonapeptide, Ac-Tyr-Arg-[Cys-Glu-His-d-Phe-Arg-Trp-Cys]-NH2 (3), led to identification of a series of novel MC-4R selective disulfide-constrained hexapeptide analogs including Ac-[hCys-His-d-Phe-Arg-Trp-Cys]-NH2 (12). The structural modifications associated with profound influence on MC-4R potency and selectivity were ring size, ring conformation, and the aromatic substitution of the d-Phe7. These cyclic peptide analogs provide novel and enhanced reagents for use in the elucidation of melanocortin-4 receptor-related physiology, and may additionally find application in the treatment of obesity and related metabolic disorders.

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