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Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model

Authors: Li-lan Sun1, Tao-yi Yang2,3, Ning-ning Wei1, Wei Lu1, Wen-xuan Jiao2,3, Qi-qi Zhou1, Yong-zhen Miao1, Qin Gao1, Xin-tong Wang2,3, Qi Sun2,3, KeWei Wang1
1 Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China
2 State Key Laboratory of Natural and Biomimetic Drugs, School of
3 Pharmaceutical Sciences, Peking University, Beijing 100191, China
Correspondence to: Qi Sun: sunqi@bjmu.edu.cn, KeWei Wang: wangkw@qdu.edu.cn,
DOI: 10.1038/s41401-018-0163-y
Received: 19 March 2018
Accepted: 27 August 2018
Advance online: 17 October 2018

Abstract

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 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-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 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 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM 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 α1β3γ2 and α5β3γ2 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 α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer’s disease.
Keywords: α7 nAChR; positive allosteric modulator; thiazolyl heterocyclic derivative; JWX-A0108; electrophysiology; prepulse inhibition of acoustic startle; spatial working memory; cognitive deficits

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