Selective M1 mAChR allosteric modulators for the treatment of schizophrenia

描述（由申请人提供）：目前的抗精神病药物治疗可以解决阳性症状，但阴性和认知症状仍然管理不善，如果有的话，是功能障碍的关键预测因素。大量的解剖学、分子学、遗传学、临床前行为学和人体临床研究提供了强有力的证据，表明能够增强胆碱能传递或激活毒蕈碱类乙酰胆碱受体（machr, M1- M5）的药物，特别是M1，在治疗精神分裂症的阳性、阴性和认知症状以及其他中枢神经系统疾病的认知功能障碍方面具有令人兴奋的治疗潜力。然而，先前开发的选择性激活M1受体的化合物由于缺乏对M1的真正特异性和与其他mAChR亚型（M2-M5）激活相关的副作用而在临床开发中失败。此外，由于缺乏高选择性化合物，因此无法明确确定这些化合物的行为和临床作用是否由M1介导。从机制上讲，令人感兴趣的是，选择性M1激活与精神分裂症的谷氨酸假说或NMDA （n -甲基- d -天冬氨酸）功能障碍假说非常吻合，因为M1和NR1a NMDA亚基在特定的突触后位点共定位，并且M1的激活是由正位的mAChR激动剂，以及最近在之前的资助期间开发的高选择性M1变构激动剂和M1阳性变构调节剂（PAMs）。增强海马切片中的NMDA电流，在临床前抗精神病啮齿动物模型中显示出强大的功效，并在多种海马驱动模型中改善认知表现。当这项拨款最初于四年前获得资助时，还没有真正的选择性M1激活剂具有必要的mAChR选择性、辅助药理学或DMPK特性来研究体内选择性M1激活的作用。因此，在之前的融资期内，我们非常成功地开发了大量高选择性M1激活剂（功能性M1选择性激动剂和代表多种化学型的M1 pam），具有前所未有的、干净的辅助药理学和DMPK谱，使体内研究能够通过功能性M1高通量筛选的化学优化来进行。基于配体偏倚的信号传导现象，为了在精神分裂症NMDA功能低下模型的背景下明确评估选择性M1激活，我们必须开发一套具有类似DMPK特性的M1配体，以激活所有M1介导的途径，以及在体内选择特定的途径。这项研究与NIMH的使命直接相关，并有可能直接影响人类健康。我们这个项目的目标是同时开发选择性M1变构激动剂和M1阳性变构调节剂，它们具有可接受的临床前和最终临床开发特征，可能导致一种用于治疗精神分裂症阳性、阴性和认知症状的新药。

DESCRIPTION (provided by applicant): Current antipsychotic therapies can address the positive symptoms, but the negative and cognitive symptoms remain poorly managed, if at all, and are key predictors of functional disability. A large number of anatomical, molecular, genetic, preclinical behavioral and human clinical studies have provided strong evidence that agents able to enhance cholinergic transmission or activate muscarinic acetylcholine receptors (mAChRs, M1- M5), notably M1, have exciting therapeutic potential for the treatment of the positive, negative and cognitive symptoms of schizophrenia as well as cognitive dysfunction in other CNS disorders. However, previous compounds developed to selectively activate M1 receptors have failed in clinical development due to a lack of true specificity for M1 and adverse effects associated with activation of other mAChR subtypes (M2-M5). Furthermore, the lack of highly selective compounds has made it impossible to definitively determine whether the behavioral and clinical effects of these compounds are mediated by M1. Mechanistically, it is intriguing that selective M1 activation fits well with the glutamate hypothesis, or NMDA (N-methyl-D-aspartate) hypofunction hypothesis of schizophrenia, as both M1 and the NR1a NMDA subunit are co-localized at specific postsynaptic sites, and activation of M1 by orthosteric mAChR agonists, and more recently, highly selective M1 allosteric agonists and M1 positive allosteric modulators (PAMs), developed during the previous funding period, potentiate NMDA currents in hippocampal slices, display robust efficacy in preclinical antipsychotic rodent models and improve cognitive performance in multiple hippocampal-driven models. When this grant was initially funded four years ago, no truly selective M1 activators existed with the requisite mAChR selectivity, ancillary pharmacology or DMPK properties to study the role of selective M1 activation in vivo. Thus, during the previous funding period, we were highly successful in developing a vast array of highly selective M1 activators (both functionally M1 selective agonists and M1 PAMs representing multiple chemotypes) with unprecedented, clean ancillary pharmacology and DMPK profiles enabling in vivo studies to be performed via the chemical optimization of hits from a functional M1 high-throughput screen. Based on ligand-biased signaling phenomena, in order to definitively evaluate selective M1 activation in the context of NMDA hypofunction models of schizophrenia, we must develop a suite of M1 ligands with comparable DMPK properties that activate all M1-mediated pathways, as well as select, specific pathways in vivo. This research has direct relevance to the mission of NIMH and has the potential to impact human health directly. Our goal for this project is to develop, in parallel, selective M1 allosteric agonists and M1 positive allosteric modulators with acceptable profiles for preclinical and ultimately clinical development that may lead to a new drug for the treatment of the positive, negative and cognitive symptoms of schizophrenia.