A Macrocyclic Agouti-Related Proteini/Nle(4),DPhe(7)alpha-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanoniolar Melanocortin Receptor Ligands

摘要

The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure activity relationship study of chimeric agouti-related protein (AGRP)/Nle4,DPhe7alpha-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative cPro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro, where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MCSR. Two compounds possessed nanomolar agonist potency at the mMC4R, cPro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro and cPro-His-DPhe-Arg-Trp-Dap-Ala-DPro, and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.