Positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M1 PAMs may reduce efficacy and contribute to adverse effect liability. However, the M1 PAM PF-06827443 was reported to have only weak agonist activity at human M1 receptors but produced M1-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M1 and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.

中文翻译：

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PF-06827443在高受体储备液和天然系统中显示稳健的变构激动剂和正变构调节剂活性。

毒蕈碱乙酰胆碱受体M1亚型的阳性变构调节剂（PAM）作为改善精神分裂症和阿尔茨海默氏病认知缺损的令人兴奋的新方法，引起了人们的浓厚兴趣。最近的证据表明，某些M1 PAM具有内在的激动剂活性可能会降低药效并导致不良反应。但是，据报道，M1 PAM PF-06827443对人M1受体仅具有弱的激动剂活性，但会产生M1依赖性的不良反应。我们现在报告PF-06827443是表达大鼠，狗和人M1的细胞系中的变构激动剂，可诱导细胞系的使用表明PF-06827443的激动剂活性取决于受体储备。此外，PF-06827443是天然组织制剂中的激动剂，可在小鼠中诱发类似于其他前PAM的行为性惊厥。这些发现表明，PF-06827443是一种功能强大的前PAM，在细胞系和天然系统中不受物种的影响。