RESUMEN

The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we have proved that the 3-position of the phenyl ring is optimal for opioid activity. Furthermore, we have successfully replaced the hydroxy group in LY255582 by carbamate and carboxamide groups. The new analogs have high affinity for the opioid receptors comparable to the corresponding phenol. Carboxamide analog 12 has an improved metabolism profile and proved to be efficacious in in vivo studies.

Asunto(s)

Antagonistas de Narcóticos/síntesis química , Piperidinas/síntesis química , Administración Oral , Animales , Ciclohexanos , Evaluación Preclínica de Medicamentos , Conducta Alimentaria/efectos de los fármacos , Ligandos , Hígado/metabolismo , Antagonistas de Narcóticos/farmacocinética , Antagonistas de Narcóticos/farmacología , Dolor/prevención & control , Fenoles , Piperidinas/farmacocinética , Piperidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad