An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission
An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission
复制标题
一种 M4 mAChR 的异位增效剂可调节海马突触传递
DOI：
10.1038/nchembio.2007.55
复制
发表时间：
2008-01-01
影响因子：
14.8
通讯作者：
Conn, P. Jeffrey
中科院分区：
文献类型：
--
作者：
Shirey, Jana K.;Xiang, Zixiu;Conn, P. Jeffrey
毒蕈碱型乙酰胆碱受体（mAChR）为治疗多种中枢神经系统疾病提供了可行的靶标。我们已经使用化学信息学和药物化学来开发新的，高选择性的M-4变构增效剂。先导化合物VU 10010使M-4对乙酰胆碱的反应增强47倍，而对其他mAChR亚型没有活性。该化合物与受体上的变构位点结合，并增加对乙酰胆碱的亲和力和与G蛋白的偶联。全细胞膜片钳记录显示，选择性增强M-4与VU 10010增加卡巴胆碱诱导的抑郁症的传输兴奋性，但不是抑制性突触在海马。该效应未被VU 10010的无活性类似物模仿，并且在M-4敲除小鼠中不存在。M4对兴奋性传递的选择性调节表明，针对单个mAChR亚型可用于差异性调节mAChR调节这一重要前脑结构功能的特定方面。
Muscarinic acetylcholine receptors (mAChRs) provide viable targets for the treatment of multiple central nervous system disorders. We have used cheminformatics and medicinal chemistry to develop new, highly selective M-4 allosteric potentiators. VU10010, the lead compound, potentiates the M-4 response to acetylcholine 47-fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for acetylcholine and coupling to G proteins. Whole-cell patch clamp recordings revealed that selective potentiation of M-4 with VU10010 increases carbachol-induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU 10010 and was absent in M-4 knockout mice. Selective regulation of excitatory transmission by M4 suggests that targeting of individual mAChR subtypes could be used to differentially regulate specific aspects of mAChR modulation of function in this important forebrain structure.