5-SUBSTITUTED BENZIMIDAZOLE DERIAVATIVES AS ANTI-STROKE AGENTS

Abstract

5-substituted benzimidazole derivatives show promise as stroke neuroprotectants with minimal adverse effects as they displayed higher selectivity for GluN2B-selective N-methyl-D-aspartate receptors over hERG channels and a1-adrenergic receptors. In this study, we report that two prototypic benzimidazole derivatives (YY1 and XK2) significantly reduced infarct volume by 40% when injected intraperitoneally 1hr prior to permanent middle cerebral artery occlusion. Neurological deficits were also generally improved in the drug-treated groups. Like XK2, YY1 reduced NMDA-induced neuronal death in rat primary cerebrocortical neurons dose-dependently. The GluN2B amino terminal domain was also shown to confer sensitivity to YY1. YY1 was also docked into the binding cleft of the GluN2B crystal structure, and binding interactions were consistent with those previously published. We also showed that the inhibition by YY1 is pH-dependent, where YY1 would function at a higher potency when pH reaches acidic levels, as would happen in the event of a stroke.