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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
  • Sun, Li-lan1
  • Yang, Tao-yi2
  • Wei, Ning-ning1
  • Lu, Wei1
  • Jiao, Wen-xuan2
  • Zhou, Qi-qi1
  • Miao, Yong-zhen1
  • Gao, Qin1
  • Wang, Xin-tong2
  • Sun, Qi2
  • Wang, KeWei1
  • 1 Qingdao University School of Pharmacy, Department of Pharmacology, Qingdao, 266021, China , Qingdao (China)
  • 2 Peking University, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Beijing, 100191, China , Beijing (China)
Type
Published Article
Journal
Acta Pharmacologica Sinica
Publisher
Springer Nature
Publication Date
Oct 17, 2018
Volume
40
Issue
6
Pages
737–745
Identifiers
DOI: 10.1038/s41401-018-0163-y
Source
Springer Nature
Keywords
License
Yellow

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.

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