RESUMO
Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin action.(1) In the hypothalamus, melanocortin peptide agonists act as satiety-inducing factors that mediate their action through the melanocortin-4 receptor (MC4R) whereas AGRP is an opposing orexigenic agent. Novel inhibitors of the AGRP/MC4 binding based on (piperazinylethyl)piperazines were prepared, and their structure-activity relationship was established.
Assuntos
Piperazinas/síntese química , Proteínas/antagonistas & inibidores , Receptores da Corticotropina/antagonistas & inibidores , Proteína Relacionada com Agouti , Sítios de Ligação , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Piperazinas/química , Piperazinas/farmacologia , Proteínas/metabolismo , Receptor Tipo 4 de Melanocortina , Receptores da Corticotropina/metabolismo , Relação Estrutura-Atividade , alfa-MSH/antagonistas & inibidores , alfa-MSH/metabolismoRESUMO
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.