ONO-8590580, a Novel GABA_Aα5 Negative Allosteric Modulator Enhances Long-Term Potentiation and Improves Cognitive Deficits in Preclinical Models

Abstract

GABA receptors containing 5 subunits (GABA5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABA5-deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABA5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABA5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl--[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human 5-containing GABA receptors with a of 7.9 nM, and showed functionally selective GABA5 NAM activity for GABA-induced Cl channel activity with a maximum 44.4% inhibition and an EC 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 GABA5 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 GABA5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update

“…The benzimidazole ONO-8590580 ( 40 , Figures and ) was recently described as an α5-GABA A R NAM . The affinity of this compound for the α5 subtype is 7.9 nM, which is around 3–30-fold higher than at α1-, α2-, or α3-GABA A Rs .…”

Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels

“…Kawaharada et al reported that ONO-8590580 was a novel selective NAM of α5β3γ2 GABA A Rs. 69 ONO-8590580 concentration-dependently inhibited GABA-induced currents in HEK293 cells expressing α5β3γ2 GABA A Rs and also interacted with the benzodiazepine site within the receptors.…”

“…This ligand dramatically enhanced GABA-induced currents of α1β2γ2 GABA A Rs by binding to the benzodiazepine site at the α + –γ – subunit that is distant from orthosteric pockets in the ECD. Kawaharada et al reported that ONO-8590580 was a novel selective NAM of α5β3γ2 GABA A Rs . ONO-8590580 concentration-dependently inhibited GABA-induced currents in HEK293 cells expressing α5β3γ2 GABA A Rs and also interacted with the benzodiazepine site within the receptors.…”

Receptor variants and the development of centrally acting medications

“…Negative allosteric modulators targeted at specific receptor subtypes might also prove beneficial as shown in a recent study conducted at a5-containing receptors. 31…”