Valproic acid and several structurally related carboxylic acids and tetrazole analogues have been shown to antagonize seizures induced by pentylenetetrazole in mice. To investigate the influence of the alkyl substituents on the anticonvulsant activity, the octanol-water partition coefficients and relative pKa values were determined. Within the series of active carboxylic acids, there was a good correlation between the anticonvulsant activity and the partition coefficient (r = 0.86). The influence of pKa on the anticonvulsant activity was small but of statistical significance. When the most active compound, 5-heptyltetrazole was added to the carboxylic acid series, a low correlation between the anticonvulsant activity and a linear combination of lipophilicity and pKa resulted. The effect of the polar moieties in alkyl-substituted anticonvulsant compounds was assessed by comparison of the regression equations with either an added pKa or dipole moment term to the term for lipophilicity. It appears that other factors, such as the nature of the alkyl substituent, influence the anticonvulsant activity. The inactivity of the cyclohexylmethyl-substituted compounds, cyclohexylacetic acid and 5-cyclohexylmethyltetrazole may be due to subtle steric effects at a critical step, either involving oxidative metabolism or an interaction at an active site.