Brouillette W J, Brown G B, DeLorey T M, Liang G
Department of Chemistry, University of Alabama, Birmingham 35294.
J Pharm Sci. 1990 Oct;79(10):871-4. doi: 10.1002/jps.2600791005.
As a preliminary investigation of the importance of the aromatic ring orientation in interactions of 5-phenylhydantoins with the anticonvulsant site on the neuronal voltage-sensitive sodium channel, two isomeric hydantoins containing conformationally constrained phenyl rings and their monocyclic analogues were synthesized. One, a spirohydantoin (2) derived from alpha-tetralone, contains the plane of the phenyl ring in an orientation approximately perpendicular to that for the hydantoin ring. The other, a tricyclic hydantoin (4) derived from tetrahydroisoquinoline, contains the plane of the phenyl ring in an orientation roughly coplanar with that for the hydantoin ring. These compounds were evaluated in sodium channel binding and whole animal (mice) anticonvulsant assays. In both assays, 4 was significantly more potent than 2, suggesting that the anticonvulsant receptor site on the voltage-sensitive sodium channel may require a specific aromatic ring orientation.
作为对5-苯基乙内酰脲与神经元电压敏感性钠通道上抗惊厥位点相互作用中芳环取向重要性的初步研究，合成了两种含有构象受限苯环的异构乙内酰脲及其单环类似物。一种是由α-四氢萘酮衍生的螺乙内酰脲（2），其苯环平面的取向与乙内酰脲环的平面大致垂直。另一种是由四氢异喹啉衍生的三环乙内酰脲（4），其苯环平面的取向与乙内酰脲环的平面大致共面。这些化合物在钠通道结合和全动物（小鼠）抗惊厥试验中进行了评估。在这两种试验中，4的效力明显高于2，这表明电压敏感性钠通道上的抗惊厥受体位点可能需要特定的芳环取向。
