PMID: 7932556Sep 30, 1994Paper

Bicyclic hydantoins with a bridgehead nitrogen. Comparison of anticonvulsant activities with binding to the neuronal voltage-dependent sodium channel

Journal of Medicinal Chemistry
W J BrouilletteG B Brown


The anticonvulsant activity of diphenylhydantoin (DPH or phenytoin) is consistent with its actions on the neuronal voltage-dependent sodium channel. To further elucidate the binding requirements for this site, we synthesized several hydantoin analogs and evaluated these in in vitro sodium channel-binding and/or in vivo whole animal anticonvulsant assays. 5-Pentyl-5-phenylhydantoin (8), the most potent binder to the sodium channel in this study, had the same affinity as DPH (IC50 = 40 microM), revealing that one phenyl ring is sufficient for good interactions. Since our previous studies with monophenyl-substituted bicyclic 2,4-oxazolidinediones suggested that N3-alkylation and the conformational constraint of a 5-alkyl substituent over one face of the oxazolidinedione ring improved activity, we synthesized two examples of analogous bicyclic hydantoins. However, the bicyclic hydantoins were much less potent binders to the neuronal voltage-dependent sodium channel than their monocyclic counterparts. The binding activity for the more potent bicyclic hydantoin, 1,8-diaza-9,10-dioxo-7-phenylbicyclo[5.2.1]decane (4) (IC50 = 427 microM), was comparable to that of the ring-opened, N3-methylated monocyclic hydantoin model, 5-butyl-3-meth...Continue Reading


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