Optically active mexiletine analogues as stereoselective blockers of voltage-gated Na+ channels
Optically active mexiletine analogues as stereoselective blockers of voltage-gated Na+ channels
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DOI：
10.1021/jm030865y
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发表时间：
2003-11-20
影响因子：
7.3
通讯作者：
De Luca, A
中科院分区：
文献类型：
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作者：
Franchini, C;Carocci, A;De Luca, A
合成了光学活性的美西律类似物，并在体外作为骨骼肌钠通道的使用依赖性阻断剂进行了评价。通过用苯基取代mexileprazole [1-（2，6-二甲基苯氧基）丙-2-胺]的立体中心上的甲基或修饰苯氧基部分（通过除去一个或两个甲基或引入氯原子）或两者来获得mexileprazole类似物。电压钳记录表明，无论芳氧基部分的取代模式如何，所有在立体异构中心（3a-f）上带有苯基的化合物在紧张性和相位性阻滞中均比美西律更活跃。该观察结果与对美西律的观察结果相反，其中从芳氧基部分去除两个甲基导致效力显著降低。最有效的同系物（R）-2-（2-甲基苯氧基）-1-苯基乙胺[（R）-3b]在产生紧张性阻滞方面比（R）-美西律强27倍，即，在应用该化合物后静息条件下峰值钠电流的降低。（R）-3b保持使用依赖性行为，在高频率刺激（相位阻滞）的条件下效力高23倍。尽管用美西律观察到了什么，但在相封闭条件下保持了立体选择性。立体选择性指数普遍较低，从1到4不等，但除了2，6-二甲苯氧基同系物3c之外，立体中心带有苯环的同系物的立体选择性指数高于美西律及其严格相关的类似物1-甲基-2-苯氧基乙胺（1）。这一发现与Pfeiffer规则一致。在芳氧基部分的4-位中引入氯原子也引起效力的降低和立体选择性的逆转。根据迄今为止接受的钠通道局部麻醉样分子受体的模型，我们的观察将提出一些可能的解释。
Optically active mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenylethanamine [(R)-3b], was 27-fold more potent than (R)-mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from I to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.