RESUMO
Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.
Assuntos
Aminoácidos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Dor/tratamento farmacológico , Receptores de Ácido Caínico/antagonistas & inibidores , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Linhagem Celular , Modelos Animais de Doenças , Humanos , Hiperalgesia/tratamento farmacológico , Ratos , Receptores de AMPA/metabolismo , Proteínas Recombinantes/metabolismo , Medula Espinal/fisiopatologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.