Muscarinic receptor activators as antipsychotic agents

描述（由申请方提供）：毒蕈碱乙酰胆碱受体（mAChR）M1亚型的选择性激动剂可能为治疗精神分裂症和其他CNS疾病患者的精神病和认知障碍提供一种新方法。不幸的是，以前的努力，以开发高选择性M1受体激动剂已经失败，因为在所有的mAChR亚型的正构乙酰胆碱结合位点的高度保守。我们现在已经开发出对任何其他mAChR亚型都没有活性的M1受体的高选择性激活剂。实现这种前所未有的选择性的关键是靶向M1上的变构位点，而不是开发作用于高度保守的ACh结合位点的传统激动剂。这些新型M1变构激活剂具有优异的药代动力学性质和脑渗透性。此外，初步研究表明，代表性化合物在动物模型中具有预测抗精神病和认知增强作用的功效。有趣的是，结构上不同的M1选择性变构激活剂可以差异调节M1的各种信号转导途径的耦合。例如，一种名为BQCA的化合物增加磷脂酶C（PLC）的M1激活、钙动员和2-抑制蛋白向细胞膜的募集。相反，其他两种M1变构激动剂，激活M1耦合PLC和钙动员，但不诱导2-arrestin募集。此外，我们的研究表明，这些药物可能差异调节M1蛋白激酶途径的偶联。这些令人惊讶的发现表明，不同的M1变构激活剂可能对CNS功能具有根本不同的作用，并且可能在其潜在的治疗效用上有所不同。因此，这将是至关重要的，以充分了解不同的M1选择性变构调节剂的M1耦合到不同的信号通路的影响，并确定这是如何涉及到这些药物的电生理效应和动物模型中的影响，预测疗效的不同领域的精神分裂症的治疗。我们将进行一系列研究，以系统地确定代表性的M1变构激活剂对细胞信号传导和前脑神经元电生理反应的影响，这些神经元对这些药物的抗精神病和认知增强作用至关重要。此外，我们将确定M1变构激活剂在啮齿动物模型中的行为效应，以预测抗精神病药物和认知增强效应。这些研究将使我们能够严格地检验这一假设，即M1的选择性变构激活剂在动物模型中具有预测作为新型抗精神病药和认知增强剂的疗效的作用。此外，我们将确定特定M1变构激活剂的电生理和行为效应是否取决于新型化合物对M1与特定细胞信号传导途径偶联的影响。

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.