Application):
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 that will lack the adverse effect of currently used antiepileptic agents. Currently, no chemical entity or 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 the investigators 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 this laboratory, with appropriate modifications. In addition, molecular modeling techniques will be employed, and the Free-Wilson analysis as detailed by P.N. Craig (J. Med. Chem. 1971, 14, 680-684 and J. Med. Chem. 1972, 15, 144-149) will be used in the development of quantitative structure-activity relationships for each moiety. Further, the new moieties and the previous analogs will be analyzed by comparative molecular field analysis-X-ray structure analysis, and in vivo determinations of the pharmacokinetics of transport of various active and inactive derivatives across the blood-brain barrier in rats will be undertaken in collaborating laboratories. An in-depth evaluation of these new classes of anticonvulsants is therefore warranted in order to study the relationship between electronic, steric, and lipophilic effects to anticonvulsant activity and pharmacokinetics so that a predictive mechanism for the feasibility of further synthetic efforts may be justified.
