The selective activation of the muscarinic M₁ receptor (M₁R) may be a promising approach for treating cognitive impairment associated with cholinergic dysfunction. We previously reported that low cooperativity (α-value) is associated with a favorable cholinergic side effect profile of M₁R positive allosteric modulators (M₁ PAMs), as well as being a crucial factor for the cognitive improvement observed after combining M₁ PAMs with donepezil, in rodents. In this study, we preclinically characterized TAK-071, a novel M₁ PAM with low cooperativity (α-value = 199), as a new therapy for schizophrenia. We tested TAK-071 in the offspring of polyriboinosinic-polyribocytidylic acid-treated dams, which is a maternal immune activation model of schizophrenia. TAK-071 improved sociability deficits and working memory in this model. In a genetic mouse model of schizophrenia, miR-137 transgenic (Tg) mice, TAK-071 improved deficits in working memory, recognition memory, sociability, and sensorimotor gating. Patients with schizophrenia usually take several antipsychotics to treat positive symptoms. Thus, we also investigated the combined effects of TAK-071 with currently prescribed antipsychotics. Among the 10 antipsychotics tested, only olanzapine and quetiapine showed M₁R antagonistic effects, which were counteracted by TAK-071 at possible effective concentrations for cognitive improvement in vitro. Moreover, haloperidol did not affect the ability of TAK-071 to improve working memory in miR-137 Tg mice, suggesting a low risk of losing efficacy when combined with dopamine D₂ receptor antagonists. In conclusion, TAK-071 can exert beneficial effects on social behavior and cognitive function and could be a new therapy for schizophrenia.

选择性激活毒蕈碱 M ₁受体 (M ₁ R) 可能是治疗与胆碱能功能障碍相关的认知障碍的一种有前途的方法。_{我们之前曾报道，低协同性（α 值）与 M 1} R 正变构调节剂 (M ₁ PAM)的有利胆碱能副作用相关，并且是结合 M ₁ PAM后观察到的认知改善的关键因素多奈哌齐，在啮齿动物中。在这项研究中，我们对 TAK-071 进行了临床前表征，这是一种新型 M ₁具有低协同性（α 值 = 199）的 PAM，作为​​精神分裂症的新疗法。我们在聚核糖-聚核糖胞苷酸处理的母体后代中测试了 TAK-071，这是一种精神分裂症的母体免疫激活模型。TAK-071 改善了该模型中的社交能力缺陷和工作记忆。在精神分裂症的遗传小鼠模型、miR-137 转基因 (Tg) 小鼠中，TAK-071 改善了工作记忆、识别记忆、社交能力和感觉运动门控方面的缺陷。精神分裂症患者通常服用几种抗精神病药来治疗阳性症状。因此，我们还研究了 TAK-071 与目前规定的抗精神病药物的联合作用。在测试的 10 种抗精神病药物中，只有奥氮平和喹硫平显示 M ₁R 拮抗作用，在可能有效的体外认知改善浓度下被 TAK-071 抵消。此外，氟哌啶醇不影响 TAK-071 改善 miR-137 Tg 小鼠工作记忆的能力，这表明与多巴胺 D 2 受体拮抗剂联合使用时失去疗效的风险_较低。总之，TAK-071 可以对社会行为和认知功能产生有益影响，可能成为精神分裂症的一种新疗法。