Muscarinic receptor activators as antipsychotic agents

描述(申请人提供)：M_1亚型乙酰胆碱受体(MAChR)选择性激动剂可能为治疗精神分裂症和其他中枢神经系统疾病患者的精神病和认知障碍提供一种新的方法。不幸的是，以前开发高选择性M1受体激动剂的努力都失败了，因为所有mAChR亚型的邻位ACh结合位点都高度保守。我们现在已经开发出高度选择性的M1受体激活剂，它对任何其他mAChR亚型都没有活性。实现这种前所未有的选择性的关键是针对M1上的变构部位，而不是开发作用于高度保守的ACh结合部位的传统激动剂。这些新型M1变构激活剂具有良好的药代动力学特性和脑渗透性。此外，初步研究表明，具有代表性的化合物在预测抗精神病和增强认知效果的动物模型中具有疗效。有趣的是，结构上不同的M1选择性变构激活剂可以不同地调节M1与不同信号通路的偶联。例如，一种名为BQCA的化合物增加了磷脂酶C(PLC)的M1激活、钙动员和2-arrestin蛋白在细胞膜上的募集。相反，另外两种M1变构激动剂激活了M1与PLC的偶联和钙动员，但不能诱导2-arrestin的募集。此外，我们的研究表明，这些药物可能不同地调节M1到蛋白激酶通路的偶联。这些令人惊讶的发现表明，不同的M1变构激活剂可能对中枢神经系统功能具有根本不同的影响，并且可能在潜在的治疗效用上有所不同。因此，充分了解不同的M1选择性变构调节剂对M1与不同信号通路的偶联的影响，并确定这与这些药物的电生理效应以及在动物模型中预测治疗精神分裂症不同领域的疗效之间的关系将是至关重要的。我们将进行一系列研究，以系统地确定具有代表性的M1变构激动剂对前脑神经元细胞信号和电生理反应的影响，这些因素对这些药物的抗精神病和增强认知作用至关重要。此外，我们还将确定M1变构激活剂在预测抗精神病药物和增强认知效果的啮齿动物模型中的行为效应。这些研究将使我们能够严格检验M1的选择性变构激活剂在动物模型中具有作用的假设，这些动物模型预测作为新型抗精神病药物和认知增强剂的疗效。此外，我们将确定特定的M1变构激活剂的电生理和行为效应是否取决于新化合物对M1与特定细胞信号通路偶联的影响。

DESCRIPTION (provided by applicant): Selective agonists of the M1 subtype of muscarinic acetylcholine receptor (mAChR) may provide a novel approach for treatment of both psychosis and cognitive disturbances in patients suffering from schizophrenia and other CNS disorders. Unfortunately, previous efforts to develop highly selective M1 receptor agonists have failed because of the high conservation of the orthosteric ACh binding site across all mAChR subtypes. We have now developed highly selective activators of the M1 receptor that have no activity at any other mAChR subtype. The key to achieving this unprecedented selectivity was to target allosteric sites on M1 rather than developing traditional agonists acting at the highly conserved ACh binding site. These novel M1 allosteric activators have excellent pharmacokinetic properties and brain penetration. Furthermore, preliminary studies suggest that representative compounds have efficacy in animal models that predict antipsychotic and cognition-enhancing effects. Interestingly, structurally distinct M1-selective allosteric activators can differentially regulate coupling of M1 to various signaling pathways. For instance, a compound termed BQCA increases M1 activation of phospholipase C (PLC), calcium mobilization, and recruitment of 2- arrestin proteins to the cell membrane. In contrast, two other M1 allosteric agonists, activate M1 coupling to PLC and calcium mobilization but do not induce 2-arrestin recruitment. In addition, our studies suggest that these agents may differentially regulate coupling of M1 to protein kinase pathways. These surprising findings suggest that distinct M1 allosteric activators could have fundamentally different effects on CNS function and could differ in their potential therapeutic utility. Thus, it will be critical to fully understand the effects of different M1-selective allosteric modulators on coupling of M1 to different signaling pathways and to determine how this relates to electrophysiological effects of these agents and effects in animal models that predict efficacy in treatment of different domains of schizophrenia. We will perform a series of studies in to systematically determine the effects of representative M1 allosteric activators on cell signaling and electrophysiological responses in forebrain neurons important for antipsychotic and cognition-enhancing effects of these agents. In addition, we will determine the behavioral effects of M1 allosteric activators in rodent models that predict antipsychotic and cognition-enhancing effects. These studies will allow us to rigorously test the hypothesis that selective allosteric activators of M1 have effects in animal models that predict efficacy as novel antipsychotic and cognition-enhancing agents. In addition, we will determine whether the electrophysiological and behavioral effects of specific M1 allosteric activators vary depending on the effects of the novel compounds on coupling of M1 to specific cell signaling pathways.