ONO-8590580, a Novel GABA A α 5 Negative Allosteric Modulator Enhances Long-Term Potentiation and Improves Cognitive Deficits in Preclinical Models

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 366; no. 1; pp. 58 - 65
• Main Authors: Kawaharada, Soichi, Nakanishi, Miki, Nakanishi, Nobuto, Hazama, Keisuke, Higashino, Masato, Yasuhiro, Tetsuya, Lewis, Arwel, Clark, Gary S, Chambers, Mark S, Maidment, Scott A, Katsumata, Seishi, Kaneko, Shuji
• Format: Journal Article
• Language: English
• Published: United States 01.07.2018
• Subjects: Allosteric Regulation - drug effects; Animals; Avoidance Learning - drug effects; Cognition - drug effects; HEK293 Cells; Hippocampus - drug effects; Hippocampus - physiology; Humans; Imidazoles - pharmacology; Long-Term Potentiation - drug effects; Male; Maze Learning - drug effects; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.117.247627

GABA receptors containing 5 subunits (GABA 5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABA 5-deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABA 5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABA 5 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 GABA 5 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 GABA 5 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 GABA 5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.