A novel benzodiazepine inverse agonist, S-8510, as a cognitive enhancer

1. Pharmacological actions of a novel benzodiazepine receptor ligand, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano+ ++[4,3-b] pyridine monophosphate monohydrate), were examined in in vitro and in vivo studies. 2. S-8510 was characterized as a partial inverse agonist with a modest GABA ratio and low efficacy. 3. S-8510 ameliorated memory impairment induced by cholinergic deficit in the water maze paradigm of Wistar rats. 4. S-8510 augmented LTP of the Schaffer collateral/commissural fiber-CA1 synapses in the hippocampal slice preparations of SD rat. 5. S-8510 increased the extracellular levels of acetylcholine and noradrenaline in the hippocampus of Wistar rat. 6. S-8510 selectively potentiated pentylenetetrazol-induced convulsion without affecting minimal electroconvulsive shock- or strychnine-induced convulsion in ddY mice. 7. S-8510 failed to induce any sign of anxiety in the Wistar rat pro-conflict test. 8. S-8510 showed antidepressant-like pharmacological actions in ddY mice. 9. These results suggest that S-8510 can be used as a therapeutic drug for senile dementia, including Alzheimer's disease with little risk for inducing anxiety or convulsion.