Over the past 40 years, the muscarinic acetylcholine receptor family, particularly the M₁-receptor and M₄-receptor subtypes, have emerged as validated targets for the symptomatic treatment of neurological diseases such as schizophrenia and Alzheimer disease. However, despite considerable effort and investment, no drugs have yet gained clinical approval. This is largely attributable to cholinergic adverse effects that have halted the majority of programmes and resulted in a waning of interest in these G-protein-coupled receptor targets. Recently, this trend has been reversed. Driven by advances in structure-based drug design and an appreciation of the optimal pharmacological properties necessary to deliver clinical efficacy while minimizing adverse effects, a new generation of M₁-receptor and M₄-receptor orthosteric agonists and positive allosteric modulators are now entering the clinic. These agents offer the prospect of novel therapeutic solutions for ‘hard to treat’ neurological diseases, heralding a new era of muscarinic drug discovery.

在过去的 40 年里，毒蕈碱乙酰胆碱受体家族，特别是 M ₁受体和 M ₄受体亚型，已成为精神分裂症和阿尔茨海默病等神经系统疾病对症治疗的有效靶标。然而，尽管付出了巨大的努力和投资，但尚未有药物获得临床批准。这主要是由于胆碱能不良反应导致大多数项目停止，并导致人们对这些 G 蛋白偶联受体靶标的兴趣减弱。最近，这一趋势得到了逆转。在基于结构的药物设计的进步以及对提供临床疗效同时最大限度地减少不良反应所需的最佳药理学特性的认识的推动下，新一代 M ₁受体和 M ₄受体正构激动剂和正变构调节剂现已进入临床领域。诊所。这些药物为“难以治疗”的神经系统疾病提供了新的治疗解决方案的前景，预示着毒蕈碱药物发现的新时代。