U-101017

U-101017 is a partial agonist of benzodiazepine receptor and GABAA receptor, with anxiolytic effects. In Vitro: PNU-101017 potentiates GABA-stimulated Cl^- currents at low concentrations (<1 μM)^[1]. U-101017 concentration-dependently inhibits the binding of [³H]FNZ to the membrane preparation of rat cerebral cortex in vitro with K_i of 3.37±0.22 nM^[2]. In Vivo: Pre-ischemic treatment with either PNU-101017 significantly protects the CA1 neuronal population, and PNU-101017 reduces the loss to 50%. Delaying PNU-101017 administration until immediately after reperfusion does not reduce the neuroprotective activity^[1]. U-101017 (30 μmol/kg, p.o.) time-dependently blocks [³H]FNZ binding to the mouse cerebral cortex. U-101017 dose-dependently decreases the levels of cGMP with ED₅₀s of 260.0 (163-425) and 0.37 (0.12-1.04) in nonstressed and foot shock-stressed mice, respectively. Flumazenil, an antagonist of GABAA receptors, has no significant effect on cGMP in nonstressed mice, but pretreatment with flumazenil significantly blocks U-101017 (10 μmol/kg, p.o.)-induced reductions in cGMP. In stressed mice, flumazenil is ineffective in altering cerebellar cGMP, but pretreatment with these doses of flumazenil significantly (p < 0.01) blocks U-101017-induced attenuation of stress-induced elevations in cGMP^[2].