The muscarinic M1 receptor (M1R) is a promising target for treating cognitive impairment associated with cholinergic deficits in disorders such as Alzheimer's disease and schizophrenia. We previously reported that cooperativity (α-value) was key to lowering the risk of diarrhea by M1R positive allosteric modulators (M1 PAMs). Based on this, we discovered a low α-value M1 PAM, TAK-071 (α-value: 199), and characterized TAK-071 using T-662 as a reference M1 PAM with high α-value of 1786. Both TAK-071 and T-662 were potent and highly selective M1 PAMs, with inflection points of 2.7 and 0.62 nM, respectively. However, T-662 but not TAK-071 augmented isolated ileum motility. TAK-071 and T-662 increased hippocampal inositol monophosphate production through M1R activation and improved scopolamine-induced cognitive deficits in rats at 0.3 and 0.1 mg/kg, respectively. TAK-071 and T-662 also induced diarrhea at 10 and 0.1 mg/kg, respectively, in rats. Thus, taking into consideration the fourfold lower brain penetration ratio of T-662, TAK-071 had a wider margin between cognitive improvement and diarrhea induction than T-662. Activation of M1R increases neural excitability via membrane depolarization, reduced afterhyperpolarization, and generation of afterdepolarization in prefrontal cortical pyramidal neurons. T-662 induced all three processes, whereas TAK-071 selectively induced afterdepolarization. Combining sub-effective doses of TAK-071, but not T-662, with an acetylcholinesterase inhibitor, significantly ameliorated scopolamine-induced cognitive deficits in rats. TAK-071 may therefore provide therapeutic opportunities for cognitive dysfunction related to cholinergic deficits or reduced M1R expression, while minimizing peripheral cholinergic side effects.

中文翻译：

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TAK-071 是一种新型 M1 正变构调节剂，具有低协同性，可改善啮齿动物的认知功能，且几乎没有胆碱能副作用。

毒蕈碱型 M1 受体 (M1R) 是治疗阿尔茨海默病和精神分裂症等疾病中与胆碱能缺陷相关的认知障碍的有前途的靶点。我们之前曾报道，协同性（α 值）是通过 M1R 阳性变构调节剂 (M1 PAM) 降低腹泻风险的关键。基于此，我们发现了低 α 值 M1 PAM，TAK-071（α 值：199），并使用 T-662 作为参考 M1 PAM 表征了 TAK-071，具有高 α 值 1786。TAK- 071 和 T-662 是有效且高选择性的 M1 PAM，拐点分别为 2.7 和 0.62 nM。然而，T-662 而不是 TAK-071 增强了离体回肠的运动性。TAK-071 和 T-662 在 0.3 和 0.1 mg/kg 剂量下通过 M1R 激活增加海马肌醇单磷酸盐的产生并改善东莨菪碱诱导的大鼠认知缺陷，分别。TAK-071 和 T-662 也分别以 10 和 0.1 mg/kg 诱导大鼠腹泻。因此，考虑到 T-662 的四倍低脑渗透率，TAK-071 在认知改善和腹泻诱导之间的差距比 T-662 更大。M1R 的激活通过膜去极化、减少后超极化和前额皮质锥体神经元中后去极化的产生来增加神经兴奋性。T-662 诱导所有三个过程，而 TAK-071 选择性诱导后去极化。将亚有效剂量的 TAK-071（而非 T-662）与乙酰胆碱酯酶抑制剂联合使用，可显着改善东莨菪碱诱导的大鼠认知缺陷。