Comparative molecular field analysis (CoMFA), a 3-D QSAR technique, is widely used to correlate biological activity with observed differences in steric and electrostatic fields. In this study, CoMFA was employed to generate a model, based upon 14 structurally diverse 5-phenylhydantoin analogues, to delineate structural and electrostatic features important for enhanced sodium channel binding. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as log IC50) and the CoMFA descriptor column generated a final non-cross-validated model with R2 = 0.988 for the training set. The final CoMFA model explained the data better than a simpler correlation with log P (R2 = 0.801) for the same training set. The CoMFA steric and electrostatic maps described two general features that result in enhanced binding to the sodium channel. These include a preferred 5-phenyl ring orientation and a favorable steric effect resulting from the C5-alkyl chain. This model was then utilized to accurately predict literature sodium channel activities for hydantoins 14-20, which were not included in the training set. Finally the hydantoin CoMFA model was used to design the structurally novel alpha-hydroxy-alpha-phenylamide 21. Synthesis and subsequent sodium channel evaluation of compound 21 (predicted IC50 = 9 microM, actual IC50 = 9 microM), a good binder to the sodium channel, established that the intact hydantion ring is not necessary for efficient binding to this site. Thus alpha-hydroxy-alpha-phenylamides may represent a new class of ligands that bind with increased potency to the sodium channel.