A novel positive allosteric modulator of the α7 neuronal nicotinic acetylcholine receptor:: In vitro and in vivo characterization
A novel positive allosteric modulator of the α7 neuronal nicotinic acetylcholine receptor:: In vitro and in vivo characterization
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DOI：
10.1523/jneurosci.5269-04.2005
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发表时间：
2005-04-27
影响因子：
5.3
通讯作者：
Arneric, SP
中科院分区：
文献类型：
--
作者：
Hurst, RS;Hajós, M;Arneric, SP
一些证据表明α 7神经元烟碱乙酰胆碱受体（nAChR）与包括精神分裂症、阿尔茨海默病和创伤性脑损伤在内的脑疾病之间存在联系。本工作描述了一种新的分子，1-（5-氯-2，4-二甲氧基-苯基）-3-（5-甲基-异恶唑-3-基）-脲（PNU-120596），它作为一个强大的正变构调节剂的α 7 nAChR。在高通量筛选中发现，PNU-120596增加了由人α 7 nAChR的工程变体介导的激动剂诱发的钙通量。电生理学研究证实，PNU-120596可增加野生型受体介导的激动剂诱发电流峰值，并且在持续存在激动剂的情况下，还可显著延长诱发反应。相比之下，PNU-120596在由α 4 β 2、β 3 β 4和α 9 α 10 nAChR介导的电流中未产生可检测的变化。PNU-120596增加了α 7 nAChR的通道平均开放时间，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增加了锥体神经元中测量的乙酰胆碱诱发的GABA能突触后电流的频率;该效应被TTX抑制，表明PNU-120596调节了位于海马中间神经元体树突膜上的α 7 nAChR的功能。因此，PNU-120596极大地增强了这些中间神经元中ACh诱发的内向电流。大鼠全身给予PNU-120596可改善安非他明引起的听觉门控缺陷，这是一种反映精神分裂症相关回路水平紊乱的模型。总之，这些结果表明，PNU-120596代表了一类新的分子，可增强α 7 nAChR功能，因此具有治疗精神和神经系统疾病的潜力。
Several lines of evidence suggest a link between the alpha 7 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 alpha 7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha 7 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 alpha 4 beta 2, beta 3 beta 4, and alpha 9 alpha 10 nAChRs. PNU-120596 increased the channel mean open time of alpha 7 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 alpha 7 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 alpha 7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.