The specific aims of the project are to synthesize new chemical compounds and evaluate them for anticonvulsant activity. The long-term objectives include the discovery of new classes of anticonvulsant agents and the development of better anticonvulsant compounds which will lack the adverse effects of currently used antiepileptic agents. Hitherto, no chemical entity, nor surgical intervention has offered a complete cure for all types of epilepsy. The research plan is designed to exploit, in a systematic manner two interesting, and hitherto unique, lead moieties developed in our laboratories: the cyclic enaminones; and the spiroimidooxy analogs. The experimental design comprises the synthesis of new compounds of each moiety, by procedures previously reported in our laboratory, with appropriate modifications. In addition, molecular modeling techniques will be employed and the Free-Wilson analysis, as detailed by P.N. Craig(1,2) will be used in the development of quantitative structure activity relationships for each moiety. Regression analysis equations will be developed to provide clarification on the roles of chirality, lipophilicity (pi), electronic (alpha) character of the substituents, dipole moment (mu), steric parameters (Es), and molar volume (Ut) exercise on anticonvulsant activity. The application of energy minimization (MM2 and MM3) as well as molecular dynamics analysis will also be used to determine the lowest energy conformer of each compound and compared to both phenytoin, and carbamazepine, each minimized, to assess root-mean-square (rms) deviation of the superimposed molecules. X-ray structure analysis, sodium channel binding analysis, and corneal and amygdala kindling data of the active compounds will be performed in collaborating laboratories.
