Recent Advances in the Modulation of Voltage-Gated Ion Channels for the Treatment of Epilepsy
Recent Advances in the Modulation of Voltage-Gated Ion Channels for the Treatment of Epilepsy
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DOI：
10.2174/1568007023339463
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发表时间：
2002-01-01
影响因子：
3
通讯作者：
Hess, Stephen D.
中科院分区：
文献类型：
--
作者：
Cosford, Nicholas D. P.;Meinke, Peter T.;Hess, Stephen D.
无论用于治疗癫痫的药物发现工作以电压门控离子通道为目标，历史上都遵循两条路线：1）最初（通常是秘密地）由于动物癫痫模型中的活性而发现的化合物通过药物化学进一步优化，或2）根据转基因动物的表型或人类与该疾病的连锁研究来鉴定分子靶点，然后在机械框架内研究化合物。主要利用第一种方法来寻找电压门控钠通道的拮抗剂；许多这些化合物对其他离子通道也具有显着的活性。这两种方法都已被用来发现电压门控钙通道拮抗剂，尽管迄今为止大多数努力都使用第一种方法。一些自发突变小鼠和转基因动物已被用来探索众多电压门控钙通道亚基及其亚型作为潜在分子靶标的作用。使用第一种方法发现了打开或延长电压门控钾通道打开的化合物，几年后对分子靶点和作用机制的详细了解逐渐显现。来自人类的遗传证据仅限于相对罕见的癫痫形式，并且具有有趣表型的转基因动物并不总是能转化为人类良好的分子靶点。迄今为止，还没有开发出临床上有用的抗癫痫药物（AED）能够特异性地与一种或什至一类离子通道相互作用以产生治疗效果。现在的工具可以寻找有效、选择性和安全的离子通道调节剂来治疗癫痫。本综述旨在总结最新的临床前和临床工作，重点关注用于 AED 开发的电压门控离子通道。
Regardless of the voltage-gated ion channel that is targeted in a drug discovery effort for the treatment of epilepsy, two routes have been followed historically: 1) a compound initially, and often surreptitiously, discovered due to activity in animal seizure models is further optimized by medicinal chemistry, or 2) a molecular target is identified based on the phenotype of transgenic animals, or linkage studies from humans with the disease, and compounds are then investigated within a mechanistic framework. Antagonists of voltage-gated sodium channels have been pursued utilizing primarily the first approach; many of these compounds also have significant activity at other ion channels. Both approaches have been utilized to discover voltage-gated calcium channel antagonists, although most efforts to date have used the first approach. Several spontaneous mutant mice and transgenic animals have been utilized to probe the role of the numerous voltage-gated calcium channel subunits and their isoforms as potential molecular targets. Compounds that open or prolong the opening of voltage-gated potassium channels have been discovered using the first approach, with a detailed understanding of the molecular target and mechanism of action coming to light several years later. Genetic evidence from humans is limited to relatively rare forms of epilepsy, and transgenic animals with interesting phenotypes do not always translate into good molecular targets in humans. No clinically-useful antiepileptic drug (AED) has been developed to date that specifically interacts with one, or even one class, of ion channels to produce a therapeutic effect. The tools now exist to search for potent, selective, and safe ion channel modulators for the treatment of epilepsy. This review seeks to summarize the most recent pre-clinical and clinical efforts focused on voltage-gated ion- channels for the development of AEDs.