alpha,alpha-Diphenylsuccinimide: evaluation of anticonvulsant and hydrophobic properties.

The anticonvulsant potencies (ED50) of alpha,alpha-diphenylsuccinimide, phenytoin, and phenobarbital were evaluated in mice by a standard maximal electroshock technique. Potencies were expressed in terms of intraperitoneal dosage and blood and brain concentrations. Overt neurotoxicity (TD50) was assessed by the rotorod method. These data were compared with relative hydrophobicities for the above compounds and three others [carbamazepine, cyheptamide, and (diphenylacetyl)urea] taken from the literature. An approximate parabolic dependence of anticonvulsant potency on hydrophobicity was observed regardless of the means of expressing potency (intraperitoneal dosage, blood concentration, or brain concentration); approximate optimal hydrophobicities were in the range of 2.18-2.23 (log P). Calculated therapeutic indices (TD50/ED50) also displayed a parabolic dependence on hydrophobicity, while toxic potency (TD50) displayed a linear dependence (within the limited range of log P values studied). Implications of the parabolic dependence of anticonvulsant potency and linear dependence of toxic potency on hydrophobicity are discussed with respect to the possible mechanisms involved.