Brouillette W J, Grunewald G L, Brown G B, DeLorey T M, Akhtar M S, Liang G
Department of Chemistry, University of Alabama, Birmingham 35294.
J Med Chem. 1989 Jul;32(7):1577-80. doi: 10.1021/jm00127a029.
Racemic 7-phenyl-9,10-dioxo-1-aza-8-oxabicyclo[5.2.1]decane (1), a bicyclic 2,4-oxazolidinedione that we previously reported was a possible sodium channel anticonvulsant, was resolved into its enantiomeric forms, the absolute configurations were determined, and the stereoisomers were evaluated for relative sodium channel binding and whole animal anticonvulsant activities. Similar studies were carried out with two monocyclic models, 5-ethyl-5-phenyl-2,4-oxazolidinedione (2) and 5-ethyl-3-methyl-5-phenyl-2,4-oxazolidinedione (3). None of these isomers exhibited stereoselective effects in the sodium channel assay, and only modest enantioselectivities were observed for 2 and 3 in the anticonvulsant assays. (R)-(-)-1 was, however, 4 times more toxic than (S)-(+)-1 in the rotorod test, and due to its larger protective index, (S)-(+)-1 exhibited greater therapeutic potential than either (R)-(-)-1 or racemic 1.
外消旋7-苯基-9,10-二氧代-1-氮杂-8-氧杂双环[5.2.1]癸烷（1），一种双环2,4-恶唑烷二酮，我们之前报道它可能是一种钠通道抗惊厥药，被拆分为其对映体形式，确定了绝对构型，并评估了这些立体异构体的相对钠通道结合能力和全动物抗惊厥活性。对两种单环模型5-乙基-5-苯基-2,4-恶唑烷二酮（2）和5-乙基-3-甲基-5-苯基-2,4-恶唑烷二酮（3）进行了类似的研究。在钠通道测定中，这些异构体均未表现出立体选择性效应，在抗惊厥测定中，仅观察到2和3有适度的对映选择性。然而，在转棒试验中，（R）-（-）-1的毒性是（S）-（+）-1的4倍，并且由于其更大的保护指数，（S）-（+）-1比（R）-（-）-1或外消旋1表现出更大的治疗潜力。
