Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M4 receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.

中文翻译：

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发现首个具有体内抗帕金森病和抗肌张力障碍功效的选择性M4毒蕈碱型乙酰胆碱受体拮抗剂

广泛抑制所有五种mAChR亚型的毒蕈碱乙酰胆碱受体（mAChR）的非选择性拮抗剂为包括帕金森病和肌张力障碍在内的某些运动障碍提供了有效的治疗方法。尽管毒蕈碱疗法在这些和其他中枢神经系统疾病中有效，但由于严重的不良反应常常限制患者对它们的耐受性，因此抗毒蕈碱疗法的应用受到限制。在理解每种mAChR亚型在疾病病理学中的作用方面的最新进展表明，使用非选择性抗毒蕈碱治疗剂所观察到的针对各个亚型的高度选择性配体可能是抗帕金森病和抗肌张力降低的基础。我们最近的工作表明，M4毒蕈碱型乙酰胆碱受体在阻止异常的神经递质释放中具有多个重要作用，细胞内信号传导途径以及与运动障碍相关的脑回路。这增加了M4的选择性拮抗剂可以概括非选择性抗毒蕈碱疗法的功效并且可以减少或消除与这些药物相关的副作用的可能性。但是，由于缺乏M4的选择性拮抗剂，因此尚未直接进行测试。在这里，我们利用基因mAChR基因敲除动物与非选择性mAChR拮抗剂相结合，以确认M4受体在啮齿动物模型中是运动刺激和抗帕金森病功效的基础。我们还报告了一流的选择性M4拮抗剂VU6013720，VU6021302的合成，发现和表征，