Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models.
Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models.
复制标题
DOI：
10.1523/jneurosci.0337-12.2012
复制
发表时间：
2012-06-20
期刊：
影响因子：
--
通讯作者：
Conn PJ
中科院分区：
文献类型：
--
作者：
Digby GJ;Noetzel MJ;Bubser M;Utley TJ;Walker AG;Byun NE;Lebois EP;Xiang Z;Sheffler DJ;Cho HP;Davis AA;Nemirovsky NE;Mennenga SE;Camp BW;Bimonte-Nelson HA;Bode J;Italiano K;Morrison R;Daniels JS;Niswender CM;Olive MF;Lindsley CW;Jones CK;Conn PJ
M1毒蕈碱型乙酰胆碱受体（mAChR）是治疗包括阿尔茨海默病和精神分裂症在内的多种中枢神经系统疾病的有效靶点。最近发现的M1受体的高选择性变构激动剂提供了一个重大突破，在开发一个可行的方法，发现新的治疗药物，这些受体的目标。在这里，我们描述了两种新型M1变构激动剂VU 0357017和VU 0364572的特征，这两种激动剂在激活M1偶联至不同信号通路（包括Ca++和β-抑制蛋白反应）的功效方面存在显著差异。有趣的是，这些代理商的能力，差异激活耦合M1特定的信号通路导致选择性行动的一些，但不是所有的M1介导的反应，在脑回路。这些新型M1变构激动剂在大鼠海马脑片中诱导了强大的电生理效应，但在纹状体中显示出较低的疗效，并且对小鼠内侧前额叶皮质锥体细胞中M1介导的反应没有可测量的影响。与这些作用一致，两种M1激动剂均增强了大鼠的海马依赖性认知功能的获得，但未逆转苯丙胺诱导的过度运动。总之，这些数据表明，M1变构激动剂可以差异调节M1与不同信号通路的偶联，这可以显著改变这些化合物对学习、记忆和精神病重要的特定脑回路的作用。
M1 muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer’s disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M1 receptors has provided a major breakthrough in developing a viable approach for discovery of novel therapeutic agents that target these receptors. Here, we describe the characterization of two novel M1 allosteric agonists VU0357017 and VU0364572 that display profound differences in their efficacy in activating M1 coupling to different signaling pathways including Ca++ and β-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M1 to specific signaling pathways leads to selective actions on some but not all M1-mediated responses in brain circuits. These novel M1 allosteric agonists induced robust electrophysiological effects in rat hippocampal slices but showed lower efficacy in striatum and no measureable effects on M1-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M1 agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M1 allosteric agonists can differentially regulate coupling of M1 to different signaling pathways and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis.