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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Allosteric modulation of the muscarinic M_4 receptor as an approach to treating schizophrenia
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Allosteric modulation of the muscarinic M_4 receptor as an approach to treating schizophrenia

机译：毒蕈碱M_4受体的变构调节作为治疗精神分裂症的一种方法

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Current antipsychotics provide symptomatic relief for patients suffering from schizophrenia and related psychoses; however, their effectiveness is variable and many patients discontinue treatment due to side effects. Although the etiology of schizophrenia is still unclear, a leading hypothesis implicates an imbalanced dopa-minergic system. Muscarinic acetylcholine (ACh) receptors regulate dopamine levels in key areas of the brain involved in psychosis, with the M_4 subtype emerging as a key regulator of dopaminergic hyperactivity. Unfortunately, no selective small molecule tools exist to provide pharmacological validation of this hypothesis. Here, we describe the discovery of a small molecule modulator, LY2033298, that is highly selective for human M_4 receptors by virtue of targeting an allosteric site on this receptor. Pharmacological assays confirmed the selectivity of LY2033298 for the M_4 receptor and revealed the highest degree of positive allosteric enhancement of ACh potency thus far identified. Radioligand binding assays also show this compound to directly potentiate agonist binding while having minimal effects on antagonist binding. Mutational analysis identified a key amino acid (D~(432)) in the third extracellular loop of the human M_4 receptor to be critical for selectivity and agonist potentiation by LY2033298. Importantly, LY2033298 was active in animal models predictive of clinical antipsychotic drug efficacy indicating its potential use as a first-in-class, selective, allosteric muscarinic antipsychotic agent.
机译：当前的抗精神病药可以为精神分裂症和相关的精神病患者提供症状缓解。然而，它们的有效性是可变的，并且许多患者由于副作用而终止治疗。尽管精神分裂症的病因尚不清楚，但是一个主要的假设暗示了多巴矿物质系统的失衡。毒蕈碱型乙酰胆碱（ACh）受体调节与精神病有关的大脑关键区域的多巴胺水平，而M_4亚型则成为多巴胺能亢进的关键调节剂。不幸的是，不存在用于提供该假设的药理学验证的选择性小分子工具。在这里，我们描述了一种小分子调节剂LY2033298的发现，它通过靶向该受体的变构位点而对人类M_4受体具有高度选择性。药理分析证实了LY2033298对M_4受体的选择性，并揭示了迄今为止已确定的ACh效力的正向变构增强程度最高。放射性配体结合测定法还显示该化合物可直接增强激动剂结合，同时对拮抗剂结合的影响最小。突变分析发现，人M_4受体第三胞外环中的关键氨基酸（D〜（432））对LY2033298的选择性和激动剂增效至关重要。重要的是，LY2033298在预测临床抗精神病药功效的动物模型中具有活性，表明其潜在地用作一流的，选择性的，变构毒蕈碱性抗精神病药。

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