A macrocyclic agouti-related protein/[Nle4,DPhe7]α-melanocyte stimulating hormone chimeric scaffold produces subnanomolar melanocortin receptor ligands

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Abstract

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,DPhe7]α-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 c[Pro-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 MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c[Pro-His-DPhe-Arg-Trp-Dap- Ala-DPro], and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.

Original languageEnglish (US)
Pages (from-to)805-813
Number of pages9
JournalJournal of medicinal chemistry
Volume60
Issue number2
DOIs
StatePublished - Jan 26 2017

Bibliographical note

Funding Information:
This work has been supported by NIH Grants R01DK091906 and R01DK097838. M.D.E. is a recipient of an NIH Postdoctoral Fellowship (Grant F32DK108402).

Publisher Copyright:
© 2017 American Chemical Society.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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