BICYCLIC HYDANTOINS WITH A BRIDGEHEAD NITROGEN - COMPARISON OF ANTICONVULSANT ACTIVITIES WITH BINDING TO THE NEURONAL VOLTAGE-DEPENDENT SODIUM-CHANNEL

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 vit ro sodium channel-binding and/or in vivo whole animal anticonvulsant a ssays. 5-Pentyl-5-phenylhydantoin (8), the mast potent binder to the s odium channel in this study, had the same affinity as DPH (IC50 = 40 m u M), revealing that one phenyl ring is sufficient for good interactio ns. Since our previous studies with monophenyl-substituted bicyclic 2, 4-oxazolidinediones suggested that N3-alkylation and the conformationa l constraint of a 5-alkyl substituent over one face of the oxazolidine dione 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 t heir 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 mu M), was comparable to that of the ring-opened, N3-me thylated monocyclic hydantoin model, 5-butyl-3-methyl-5-phenylhydantoi n (9) (IC50 = 285 mu M), and these were 8-11 times less potent than th e monocyclic model 8, which contains a free imide NH. Furthermore, 5-b utyl-5-phenylhydantoin (7; IC50 = 103 mu M) was less potent than 8, su ggesting that increased log P may enhance binding. Thus, unlike 2,4-ox azoldinediones, N3-alkylation of hydantoins dramatically decreases sod ium channel-binding activity. Bicyclic hydantoin 4 was nevertheless a good anti-MES anticonvulsant in mice (ED(50) = 86 mg/kg), although thi s activity likely results from mechanisms other than interactions at t he neuronal voltage-dependent sodium channel. Compound 4 was also rela tively neurotoxic (TD50 = 124 mg/kg). These results suggest that the b inding of hydantoins to the sodium channel may be enhanced by (a) a fr ee imide NH group and (b) an increased log P. Furthermore, 2,4-oxazoli dinediones and hydantoins must either orient differently in the same b inding site or interact with different sites on the neuronal voltage-d ependent sodium channel.