RT Journal Article
SR Electronic
T1 ONO-8590580, a Novel GABA<sub>A</sub> <em>α</em>5 Negative Allosteric Modulator Enhances Long-Term Potentiation and Improves Cognitive Deficits in Preclinical Models
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 58
OP 65
DO 10.1124/jpet.117.247627
VO 366
IS 1
A1 Soichi Kawaharada
A1 Miki Nakanishi
A1 Nobuto Nakanishi
A1 Keisuke Hazama
A1 Masato Higashino
A1 Tetsuya Yasuhiro
A1 Arwel Lewis
A1 Gary S. Clark
A1 Mark S. Chambers
A1 Scott A. Maidment
A1 Seishi Katsumata
A1 Shuji Kaneko
YR 2018
UL http://jpet.aspetjournals.org/content/366/1/58.abstract
AB GABAA receptors containing α5 subunits (GABAA α5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABAA α5–deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABAA α5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABAA α5 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 α5–containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAA α5 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 GABAA α5 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 GABAA α5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.