Molecular interactions of nonpeptide agonists and antagonists with the melanocortin-4 receptor.

The melanocortin-4 (MC4) receptor is a potential therapeutic target for obesity and cachexia, for which nonpeptide agonists and antagonists are being developed, respectively. The aim of this study was to identify molecular interactions between the MC4 receptor and nonpeptide ligands, and to compare the mechanism of binding between agonist and antagonist ligands. Nonpeptide ligand interaction was affected by mutations that reduce peptide ligand binding (D122A, D126A, S190A, M200A, F261A, and F284A), confirming overlapping binding determinants for peptide and nonpeptide ligands.

Structure-activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor.

SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency.