Pharmacological characterization of JWX-A0108 as a novel type Ⅰ positive allosteric modulator of a7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model  

作　　者：Li-lan Sun Tao-yi Yang Ning-ning Wei Wei Lu Wen-xuan Jiao Qi-qi Zhou Yong-zhen Miao Qin Gao Xin-tong Wang Qi Sun KeWei Wang 

机构地区：[1]Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China [2]State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

出　　处：《Acta Pharmacologica Sinica》2019年第6期737-745,共9页中国药理学报（英文版）

基　　金：research grants to KWW and Q S from the National Natural Science Foundation of China (NSFC 81573410,31370741, and 21572011);Ministry of Science and Technology of China (2013CB531302).

摘　　要：The a7 nicotinic acetylcholine receptor (a7 nAChR) is a ligand-gated Ca^2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of a7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6- methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-cflpyrimiclin-7(6H)-one (JWX-A0108), as a novel type I a7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 seleaively enhanced a7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ±0.12 pM). In hippocampal slices, co-application of ACh and JWXA0108 (10 pM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAa receptor aip3y2 and a5(33Y2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80,84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type Ⅰ PAM of a7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.

关 键 词：a7 NACHR positive ALLOSTERIC modulator thiazolyl HETEROCYCLIC derivative JWX-A0108 electrophysiology PREPULSE inhibition of ACOUSTIC STARTLE spatial working memory cognitive deficits 

分 类 号：R[医药卫生]