Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives
Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives
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DOI：
10.1021/jm980627g
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发表时间：
1999-07-15
影响因子：
7.3
通讯作者：
Soares-da-Silva, P
中科院分区：
文献类型：
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作者：
Benes, J;Parada, A;Soares-da-Silva, P
合成了奥卡西平(2)的主要代谢物10，11-二氢-10-羟基-5H-二苯并[b，f]氮杂卓-5-甲酰胺的一系列酯类化合物，并对其抗惊厥和脑钠通道阻断性能进行了评价。通过大鼠腹腔注射和口服这些化合物来对抗最大电休克(MES)诱发的癫痫发作。用旋转棒试验评定神经功能缺损程度。对映体醋酸酯(R)-11和(S)-12对MES致痫的作用最强，口服ED50值分别为10.9+/-2.3和4.7+/-9 mg/kg。在给药后，卡马西平(1)在MES试验中表现出比2和所有其他新的二苯并[b，f]氮杂-5-甲酰胺衍生物更强的效力；化合物2和12的效力相同。在旋转棒试验中，低剂量的1.产生相当大的运动损伤，而2，对映醇(S)-6；，(R)-7，外消旋醇，或外消旋醋酸酯10或(R)-11不发生这种损害。由2衍生的外消旋和对映体纯醇8、(S)-6和(R)-7在MES和Rotod测试中的效力相似，因此它们表现出相似的保护指数值。在MES或旋转棒试验中，发现所有三种形式的酒精及其相应的乙酸酯(对8和10，6和12，以及7和11)都不同；(S)-6对MES诱导的癫痫的ED50值几乎是(S)-12的3倍。乙醇的所有立体异构体与其对应的乙酸酯之间的保护指数也有显著差异，其中化合物(S)-12的保护指数最高，为12.5。通过研究[H-3]-巴曲霉毒素A 20-α-苯甲酸酯([H-3]-BTX)的结合，研究了对电压敏感钠通道的阻断作用。乙酸酯(R)-11和(S)-12比标准1和-2更能抑制[H-3]BTX与钠通道的结合和Na-22(+)内流到大鼠脑突触体。结论：乙酸酯(R)-11和(5)-12不是醇(R)-7和(S)-6在啮齿动物体内的简单代谢前体，它们本身具有抗惊厥和钠通道阻断作用。
A. series of esters of the major metabolite of oxcarbazepine (2), 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED50 values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1. produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6;, (R)-7, and racemic alcohol, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED50 value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [H-3]-batrachotoxinin A 20-alpha-benzoate ([H-3]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and-2 at inhibiting the binding of [H-3]BTX to sodium channels and the influx: of Na-22(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (5)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.