Muscarinic receptor activators as antipsychotic agents

描述（由申请人提供）：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的治疗提供一种新的方法。不幸的是，之前开发高选择性M1受体激动剂的努力失败了，因为所有mAChR亚型的正位乙酰胆碱结合位点高度保守。我们现在已经开发了M1受体的高选择性激活剂，它在任何其他mAChR亚型中都没有活性。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穿透性。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增强认知作用的功效。有趣的是，结构上不同的M1选择性变构激活剂可以不同地调节M1与各种信号通路的耦合。例如，一种被称为BQCA的化合物增加了磷脂酶C （PLC）的M1激活、钙动员和2-阻滞蛋白向细胞膜的募集。相比之下，另外两种M1变构激动剂可以激活M1与PLC的偶联和钙动员，但不会诱导2-停搏蛋白的募集。此外，我们的研究表明，这些药物可能不同地调节M1与蛋白激酶途径的偶联。这些令人惊讶的发现表明，不同的M1变构激活剂可能对中枢神经系统功能具有根本不同的影响，并且可能具有不同的潜在治疗效用。因此，充分了解不同M1选择性变张调节剂对M1与不同信号通路耦合的影响，并确定这与这些药物的电生理效应和动物模型中预测精神分裂症不同领域治疗效果的影响之间的关系，将是至关重要的。我们将在2010年进行一系列研究，系统地确定代表性M1变构激活剂对前脑神经元细胞信号传导和电生理反应的影响，这些药物对抗精神病和增强认知的作用很重要。此外，我们将在啮齿动物模型中确定M1变构激活剂的行为效应，以预测抗精神病和增强认知的作用。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预测新型抗精神病药和认知增强剂功效的假设。此外，我们将确定特异性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.