Brouillette W J, Brown G B, DeLorey T M, Shirali S S, Grunewald G L
Department of Chemistry, University of Alabama, Birmingham 35294.
J Med Chem. 1988 Nov;31(11):2218-21. doi: 10.1021/jm00119a025.
8,9-Dioxo-6-phenyl-1-aza-7-oxabicyclo[4.2.1]nonane (1) and 9,10-dioxo-7-phenyl-1-aza-8-oxabicyclo[5.2.1]decane (2), examples of anti-Bredt bicyclic 2,4-oxazolidinediones, were investigated as anticonvulsants in mice. Compound 2 was the more potent (anti-MES ED50 = 66 mg/kg), and its in vivo anti-MES effect was consistent with its in vitro potency of binding to the voltage-sensitive sodium channel (IC50 = 160 microM for the inhibition of binding of [3H]BTX-B), suggesting that 2 may be a new class I anticonvulsant. Several partial structures of 2, either monocyclic lactams or monocyclic 2,4-oxazolidinediones, were also evaluated in these assays, but no correlation was observed between sodium channel binding and anti-MES effects. A significant finding was that monocyclic 5-alkyl-5-phenyl-2,4-oxazolidinediones provided relatively potent, nontoxic, broad-spectrum anticonvulsants.
8,9-二氧代-6-苯基-1-氮杂-7-氧杂双环[4.2.1]壬烷（1）和9,10-二氧代-7-苯基-1-氮杂-8-氧杂双环[5.2.1]癸烷（2）是抗布雷德特双环2,4-恶唑烷二酮的实例，作为抗惊厥药在小鼠中进行了研究。化合物2的活性更强（抗最大电休克发作半数有效剂量=66毫克/千克），其体内抗最大电休克发作作用与其体外与电压敏感性钠通道结合的活性一致（抑制[3H]BTX-B结合的半数抑制浓度=160微摩尔），这表明2可能是一种新型I类抗惊厥药。2的几种部分结构，即单环内酰胺或单环2,4-恶唑烷二酮，也在这些试验中进行了评估，但未观察到钠通道结合与抗最大电休克发作作用之间的相关性。一个重要发现是单环5-烷基-5-苯基-2,4-恶唑烷二酮提供了相对强效、无毒的广谱抗惊厥药。
