Structure-activity relationships of peptides incorporating a bioactive reverse-turn heterocycle at the melanocortin receptors: Identification of a 5800-fold mouse melanocortin-3 receptor (mMC3R) selective antagonist/partial agonist versus the mouse melanocortin-4 receptor (mMC4R)

Anamika Singh, Marvin Dirain, Rachel Witek, James R. Rocca, Arthur S. Edison, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The melanocortin-3 (MC3) and melanocortin-4 (MC4) receptors regulate energy homeostasis, food intake, and associated physiological conditions. The melanocortin-4 receptor (MC4R) has been studied extensively. Less is known about specific physiological roles of the melanocortin-3 receptor (MC3R). A major obstacle to this lack of knowledge is attributed to a limited number of identified MC3R selective ligands. We previously reported a spatial scanning approach of a 10-membered thioether-heterocycle ring incorporated into a chimeric peptide template that identified a lead nM MC4R ligand. Upon the basis of those results, 17 compounds were designed and synthesized that focused upon modification in the pharmacophore domain. Notable results include the identification of a 0.13 nM potent 5800-fold mMC3R selective antagonist/slight partial agonist versus a 760 nM mMC4R full agonist (ligand 11). Biophysical experiments (two-dimensional 1H NMR and computer-assisted molecular modeling) of this ligand resulted in the identification of an inverse γ-turn secondary structure in the ligand pharmacophore domain.

Original languageEnglish (US)
Pages (from-to)2747-2763
Number of pages17
JournalJournal of medicinal chemistry
Volume56
Issue number7
DOIs
StatePublished - Apr 11 2013

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