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.

中文翻译：

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JWX-A0108作为α7nAChR的新型I型正变构调节剂的药理学表征，可以逆转小鼠前脉冲抑制模型中的声门控缺陷。

α7烟碱乙酰胆碱受体（α7nAChR）是配体门控的可渗透Ca2 +的同五聚体离子通道，与认知和神经精神疾病有关。已提出药理学增强α7nAChR功能可改善认知功能障碍。在本研究中，我们表征了噻唑基杂环衍生物6-（2-氯-6-甲基苯基）-2-（（3-氟-4-甲基苯基）氨基）噻唑并[4,5-d]嘧啶-7（ 6H）-一（JWX-A0108）作为新型I型α7nAChR阳性变构调节剂（PAM），并评估了其逆转小鼠听觉门控和空间工作记忆缺陷的能力。在表达人类nAChR通道的非洲爪蟾卵母细胞中，在存在激动剂ACh的情况下（EC50值= 4.35±0.12 µM），JWX-A0108的应用选择性地增强了α7nAChR介导的内向电流。在海马片中 共同应用ACh和JWX-A0108（每个10 µM）显着增加了锥体神经元中记录的自发抑制性突触后电流（sIPSCs）的频率和幅度，但JWX-A0108不会影响表达人卵母细胞中GABA诱导的电流GABAA受体α1β3γ2和α5β3γ2亚型。在患有MK-801引起的听觉门控缺陷的小鼠中，JWX-A0108（1、3和10 mg / kg，腹腔注射）的剂量依赖性地减弱了五种脉冲前强度下MK-801引起的听觉门控缺陷（72， 76、80、84和88 dB）。此外，JWX-A0108（0.03、0.1或0.3 mg / kg，腹腔注射）的给药显着逆转了MK-801诱导的小鼠空间工作记忆受损。我们的结果表明，JWX-A0108是α7nAChR的新型I PAM，