Optical Control of Acetylcholinesterase with a Tacrine Switch
Optical Control of Acetylcholinesterase with a Tacrine Switch
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DOI：
10.1002/anie.201403666
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发表时间：
2014-07-14
影响因子：
16.6
通讯作者：
Trauner, Dirk
中科院分区：
文献类型：
--
作者：
Broichhagen, Johannes;Jurastow, Innokentij;Trauner, Dirk
光致变色配体已被用于控制各种生物功能，特别是在神经系统中。近年来，在突触中发现的离子通道和G蛋白偶联受体的光控制方面投入了大量的努力。在这里，我们描述了我们的远程控制酶的药理学方法的扩展。基于20世纪60年代末的标志性研究，我们评估了突触传递中最重要的酶之一乙酰胆碱酯酶（AChE）的光致变色抑制剂。采用基于结构的设计，我们合成了几个偶氮苯类似物的著名的乙酰胆碱酯酶抑制剂他克林（THA），并确定其对酶活性的影响。我们的化合物之一AzoTHA是体外和离体AChE的可逆光致变色阻断剂，具有高亲和力和快速动力学。因此，AzoTHA可用于基于神经递质的光依赖性清除来控制神经肌肉终板上的突触传递。
Photochromic ligands have been used to control a variety of biological functions, especially in neural systems. Recently, much effort has been invested in the photocontrol of ion channels and G-protein coupled receptors found in the synapse. Herein, we describe the expansion of our photopharmacological approach toward the remote control of an enzyme. Building on hallmark studies dating from the late 1960s, we evaluated photochromic inhibitors of one of the most important enzymes in synaptic transmission, acetylcholinesterase (AChE). Using structure-based design, we synthesized several azobenzene analogues of the well-known AChE inhibitor tacrine (THA) and determined their effects on enzymatic activity. One of our compounds, AzoTHA, is a reversible photochromic blocker of AChE in vitro and ex vivo with high affinity and fast kinetics. As such, AzoTHA can be used to control synaptic transmission on the neuromuscular endplate based on the light-dependent clearance of a neurotransmitter.