RT Journal Article SR Electronic T1 ONO-8590580, a novel GABAA α5 negative allosteric modulator enhances long-term potentiation and improves cognitive deficits in preclinical models. JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.117.247627 DO 10.1124/jpet.117.247627 A1 Soichi Kawaharada A1 Miki Nakanishi A1 Nobuto Nakanishi A1 Keisuke Hazama A1 Masato Higashino A1 Arwel Lewis A1 Gary S Clark A1 Mark S Chambers A1 Scott A Maidment A1 Tetsuya Yasuhiro A1 Seishi Katsumata A1 Shuji Kaneko YR 2018 UL http://jpet.aspetjournals.org/content/early/2018/04/19/jpet.117.247627.abstract AB GABAA receptors containing α5 subunits (GABAA α5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABAA α5 deficient mice show higher hippocampus-dependent performance than wild type mice. Accordingly, small molecule GABAA α5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally-available GABAA α5 NAM that improves hippocampal functions. ONO-8590580 binds to the benzodiazepine binding sites on recombinant human α5-containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAA α5 NAM activity for GABA-induced Cl- channel activity with a maximum 44.4% inhibition and an EC50 of 1.1 nM. In rat hippocampal slices, tetanus-induced long-term potentiation of CA1 synapse response was significantly augmented in the presence of 300 nM ONO-8590580. Orally administered ONO-8590580 (1-20 mg/kg) dose-dependently occupied hippocampal GABAA α5 in a range of 40-90% at 1 h after intake. In the rat passive avoidance test, ONO-8590580 (3-20 mg/kg, p.o.) significantly prevented MK-801-induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving cognitive deficit induced by scopolamine and MK-801 in the rat 8-arm radial maze test with equal or greater activity than 0.5 mg/kg donepezil. No anxiogenic-like or proconvulsant effect was associated with ONO-8590580 at 20 mg/kg, p.o. in the elevated plus maze test or pentylenetetrazole-induced seizure test, respectively. In sum, ONO-8590580 is a novel GABAA α5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.