ONO-8590580, a novel GABA A a5 negative allosteric modulator enhances long-term potentiation and improves cognitive deficits in preclinical models

Abstract

GABA A receptors containing a5 subunits (GABA A a5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABA A a5–deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABA A a5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABA A a5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl-N-[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human a5–containing GABA A receptors with a K i of 7.9 nM, and showed functionally selective GABA A a5 NAM activity for GABA-induced Cl 2 channel activity with a maximum 44.4% inhibition and an EC 50 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 GABA A a5 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 (1)-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 GABA A a5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.