RESUMEN
Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
Asunto(s)
Analgésicos/síntesis química , Bencimidazoles/química , Neuralgia/tratamiento farmacológico , Pirroles/química , Receptores Opioides/agonistas , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Microsomas Hepáticos/metabolismo , Pirroles/farmacocinética , Pirroles/uso terapéutico , Ratas , Receptores Opioides/metabolismo , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A novel potent NMDA-NR2B selective antagonist without the reactive metabolites formation issue was identified. Through this study, a close correlation between reactive metabolites formation and calculated HOMO energies of parent compounds was found.