A series of ureides active against grand mal epilepsy have been studied by using classical potential energy calculations. The series includes phenyl ethyl and diphenyl derivatives of hydantoins, succinimides, glutarimides, oxazolidine-2,4-diones, pyrimidine-2,6-diones, barbituric acids, and phenacemide. A thorough examination of the conformational possibilities did not reveal an exclusive conformation that could account for their activity. However, comparisons with diazepam and other benzodiazepines known to have the ability to competitively bind with drugs such as diphenylhydantoin at some sites show that there is a distinct conformational preference that may well account for their activity against grand mal epilepsy. The conformational studies led to the proposal of a general model for anticonvulsant activity comprising two aromatic rings or their equivalent in a favored orientation and a third region, usually a cyclic ureide, comprising a number of hydrogen-bond-forming functional groups. The specific placement of hydrogen-bonding groups in this region appears to be of less importance than the correct conformational arrangement of the hydrophobic elements.

Anticonvulsant drugs come from a range of chemical types, but most drugs show important structural features in common. I t has been suggested elsewhere that molecular conformation may be an important factor in determining activity. The present work has been designed to investigate the influence of both stereochemistry and clcctronic structure on anticonvulsant action. Empirical potential energy calculations are first used to determine preferred conformations. It is found that anticonvulsants adopt a common preferred conformation. which is likely to be responsible for anticonvulsant activity. Molecular electrostatic potentials are also calculated for iinticonvulsants. Lifter first being evaluated in a series of model compounds. Electrostatic potentials based on M I N D O /~ wave functions are found to be well suited to molecules containing carbonyl groups. and are also able to provide a quantitative estimate of reactivity. Applications to anticonvuIs:ints shows the existence of a common electrostatic field. where similar regions of positive and negative potential are seen throughout the series studied.The structure-activity relationship outlined here applies to anticonvulsant activity against experimental clectroshock seizures, and associated clinical use in the treatment of tonic-clonic (grand m i l ) epilepsy. I t appears that both stereochcmical and electronic factors play an important role in determining the activity of anticonvulsant drugs.

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