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首页> 外文期刊>Biochemical Pharmacology >Comparative pharmacology and computational modelling yield insights into allosteric modulation of human alpha7 nicotinic acetylcholine receptors.
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Comparative pharmacology and computational modelling yield insights into allosteric modulation of human alpha7 nicotinic acetylcholine receptors.

机译：比较药理学和计算模型产生洞察人类α7烟碱乙酰胆碱受体的变构调节。

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摘要

The human alpha7 nicotinic acetylcholine receptor (nAChR) subunit and its Caenorhabditis elegans homolog, ACR-16, can generate functional recombinant homomeric receptors when expressed in Xenopus laevis oocytes. Both nAChRs express robustly in the presence of the co-injected chaperone, RIC-3, and show striking differences in the actions of a type I positive allosteric modulator (PAM), ivermectin (IVM). Type I PAMs are characterised by an increase in amplitude only of the response to acetylcholine (ACh), whereas type II PAMs exhibit, in addition, changes in time-course/desensitization of the ACh response. The type I PAMs, ivermectin, 5-hydroxyindole (5-HI), NS-1738 and genistein and the type II PAM, PNU-120596, are all active on human alpha7 but are without PAM activity on ACR-16, where they attenuate the amplitude of the ACh response. We used the published structure of avermectin B1a to generate a model of IVM, which was then docked into the candidate transmembrane allosteric binding site on alpha7 and ACR-16 in an attempt to gain insights into the observed differences in IVM actions. The new pharmacological findings and computational approaches being developed may inform the design of novel PAM drugs targeting major neurological disorders.
机译：当在非洲爪蟾卵母细胞中表达时，人α7烟碱型乙酰胆碱受体（nAChR）亚基及其秀丽隐杆线虫的同源物ACR-16可以产生功能性重组同源受体。两种nAChRs在共同注射的伴侣RIC-3的存在下均能稳定表达，并且在I型正变构调节剂（PAM），伊维菌素（IVM）的作用中表现出惊人的差异。 I型PAM的特征在于仅对乙酰胆碱（ACh）的响应的幅度增加，而II型PAM另外显示出ACh响应的时程/脱敏性的变化。 I型PAM，伊维菌素，5-羟基吲哚（5-HI），NS-1738和染料木黄酮和II型PAM，PNU-120596对人alpha7均具有活性，但对ACR-16却没有PAM活性，从而使它们减弱ACh响应的幅度。我们使用阿维菌素B1a的已发布结构生成了IVM模型，然后将其对接到alpha7和ACR-16上的候选跨膜变构结合位点，以试图深入了解所观察到的IVM动作差异。正在开发的新药理学发现和计算方法可能会为针对主要神经系统疾病的新型PAM药物的设计提供信息。

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