Binding to the neuronal voltage-dependent sodium channel (NVSC) was evaluated for 12 5-phenylhydantoins which systematically varied either log P and/or 5-phenyl ring orientation. The linear correlation of log P with in vitro sodium channel binding activity (log IC50) for hydantoins 1-12 and diphenylhydantoin (DPH) (r2 = 0.638) suggested that simple partitioning into the lipid phase is important but not sufficient to account for the effects of hydantoins on the NVSC. Comparisons among different hydantoins with the same log P but different low-energy phenyl ring orientations revealed that, in addition to log P, the correct 5-phenyl orientation is important for efficient binding.