RESUMO
The biological activity for a set of melanocortin-4 receptor (MC4R) agonists containing a piperazine core with an ortho-substituted aryl sulfonamide is described. Compounds from this set had binding and functional activities at MC4R less than 30 nM. The most selective compound in this series was >25,000-fold more potent at MC4R than MC3R, and 490-fold more potent at MC4R than MC5R. This compound also reduced food intake after oral dosing at 25, 50, and 100 mg kg(-1) in fasted mice.
Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Ligação Competitiva , Comportamento Alimentar/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2) (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, DPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC(50) and EC(50) below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors.