Sodium channel binding and anticonvulsant activities of hydantoins containing conformationally constrained 5-phenyl substituents

• Published in: Journal of pharmaceutical sciences Vol. 79; no. 10; p. 871
• Main Authors: Brouillette, W J, Brown, G B, DeLorey, T M, Liang, G
• Format: Journal Article
• Language: English
• Published: United States 01.10.1990
• Subjects: Animals; Anticonvulsants; Hydantoins - chemistry; Hydantoins - metabolism; Hydantoins - pharmacology; In Vitro Techniques; Male; Molecular Conformation; Rats; Sodium Channels - metabolism; Synaptosomes - drug effects
• ISSN: 0022-3549
• 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.