Conformational analysis of clinically active anticonvulsant drugs

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.