...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
【24h】

A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.

机译：新型的α7神经元烟碱乙酰胆碱受体的正变构调节剂：体外和体内表征。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Several lines of evidence suggest a link between the alpha7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the alpha7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by alpha4beta2, alpha3beta4, and alpha9alpha10 nAChRs. PNU-120596 increased the channel mean open time of alpha7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of alpha7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances alpha7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.
机译：几条证据表明，α7神经元烟碱型乙酰胆碱受体（nAChR）与包括精神分裂症，阿尔茨海默氏病和脑外伤在内的脑部疾病之间存在联系。本工作描述了一种新型分子1-（5-氯-2,4-二甲氧基-苯基）-3-（5-甲基-异恶唑-3-基）-尿素（PNU-120596） α7nAChR的正变构调节剂。在高通量筛选中发现，PNU-120596增加了由人alpha7 nAChR的工程变体介导的激动剂诱发的钙通量。电生理研究证实，PNU-120596增加了由野生型受体介导的激动剂诱发的峰值电流，并且还表明在持续存在激动剂的情况下，诱发的反应明显延长。相反，PNU-120596在由alpha4beta2，alpha3beta4和alpha9alpha10 nAChRs介导的电流中未产生可检测的变化。 PNU-120596增加了alpha7 nAChRs的通道平均打开时间，但对离子选择性没有影响，对单位电导的影响相对较小（如果有的话）。当应用于急性海马切片时，PNU-120596可增加在锥体神经元中测量的ACh诱发的GABA能突触后突触电流的频率。 TTX抑制了这种作用，表明PNU-120596调节了位于海马中间神经元体树突状膜上的alpha7 nAChR的功能。因此，PNU-120596大大增强了这些中间神经元中ACh诱发的内向电流。对大鼠的全身给药PNU-120596改善了由苯丙胺引起的听觉门控缺陷，该模型被提出来反映与精神分裂症相关的电路水平障碍。总之，这些结果表明，PNU-120596代表了一类新的分子，可以增强alpha7 nAChR功能，因此具有治疗精神病和神经病的潜力。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号