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

摘要

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 (slPSCs) recorded in pyramidal neurons,but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor cα1β3γ2 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.