RESUMEN
A novel and facile domino reaction has been developed to synthesize a variety of new derivatives from hydromorphone, amines and paraformaldehyde in good yields in a catalyst-free fashion with high atom efficiency. The products show a mixed MOR/DOR biological characteristic which makes them valuable for further study as opioid analgesics.
Asunto(s)
Analgésicos Opioides/farmacología , Derivados de la Morfina/farmacología , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/química , Animales , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Derivados de la Morfina/administración & dosificación , Derivados de la Morfina/química , Receptores Opioides kappa/deficiencia , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/deficiencia , Relación Estructura-ActividadRESUMEN
To optimize the structure of a µ-opioid receptor ligand, analogs H-Tyr-c[D-Lys-Xxx-Tyr-Gly] were synthesized and their biological activity was tested. The analog containing a Phe(3) was identified as not only exhibiting binding affinity 14-fold higher than the original hit but also producing agonist activity 3-fold more potent than morphine. NMR study suggested that a trans conformation at D-Lys(2)-Xxx(3) is crucial for these cyclic peptides to maintain high affinity, selectivity, and functional activity toward the µ-opioid receptor.