Sodium channel blocking, anticonvulsant activity, and sigma (sigma) binding of selected leads in a series of alpha-amino amide anticonvulsants were examined. While anticonvulsant compounds were always endowed with low micromolar sodium (Na+) channel site-2 binding, compounds with low site-2 Na+ channel affinity failed to control seizures. No correlation could be drawn with sigma1 binding. Both anticonvulsant and Na+ channel blocking activities were independent of stereochemistry, while sigma1 binding seems to be favoured by an S-configuration on the aminoamide moiety.