ONO-8590580

ONO-8590580 is a negative allosteric modulator of α₅ subunit-containing GABA_A receptors that binds at the benzodiazepine binding site.¹ It binds to α₁, α₂, α₃, and α₅ subunit-containing GABA_A receptors (K_is = 140, 32, 24, and 7.9 nM, respectively). It is selective for inhibiting GABA-induced currents in HEK293 cells expressing human recombinant α₅β₃γ₂ subunits (EC₅₀ = 1.1 nM) over those expressing human recombinant α₁β₃γ₂, α₂β₃γ₂, or α₃β₃γ₂ subunits for which it has little to no activity. ONO-8590580 (300 nM) enhances long-term potentiation in rat hippocampal brain slices. It decreases MK-801-induced memory deficits in the rat passive avoidance test when administered at doses ranging from 3 to 20 mg/kg. ONO-8590580 (20 mg/kg, p.o.) decreases MK-801- and scopolamine-induced increases in the latency to complete, and the number of errors made in, the eight-arm radial maze test in rats. It does not induce anxiety-like or proconvulsant behavior in rats in the elevated zero maze or pentylenetetrazole-induced seizure test when administered at a dose of 20 mg/kg.

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1. Kawaharada, S., Nakanishi, M., Nakanishi, N., et al. ONO-8590580, a novel GABA_A α5 negative allosteric modulator enhances long-term potentiation and improves cognitive deficits in preclinical models. J. Pharmacol. Exp. Ther. 366(1), 58-65 (2018).