ONO-8590580

Description: ONO-8590580 is a novel and potent GABAAalpha5 negative allosteric modulator which enhances long-term potentiation and improves cognitive deficits in preclinical models. ONO-8590580 binds to the benzodiazepine binding sites on recombinant human alpha5-containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAAalpha5 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 GABAAalpha5 in a range of 40%-90% at 1 hour after intake. In the rat passive avoidance test, ONO-8590580 (3-20 mg/kg, by mouth) significantly prevented (+)-MK-801 hydrogen maleate (MK-801)-induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving the cognitive deficit induced by scopolamine and MK-801 in the rat eight-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 GABAAalpha5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.

References: J Pharmacol Exp Ther. 2018 Jul; 366(1):58-65.