The Development of Exogenous Anticonvulsants and Endogenous Uracil-Based Antiepileptic Agents

Abstract

Epilepsy is a common neurological disorder for which the development of new and improved therapies is essential. Thus, the central theme of this thesis pertains to the design and synthesis of putative antiepileptic drugs. A substructure search was performed on a database of exogenous compounds to find those that contain a known sodium channel pharmacophore. The anticonvulsant activity of several compounds identified by this search was evaluated, resulting in the recognition of multiple molecular classes from which new anticonvulsant scaffolds could be derived. A series of analogues derived from uracil (an endogenous molecule) were synthesized and evaluated for anticonvulsant activity. Several of these analogues displayed promising activity and minimal toxicity, further supporting the theory that uracils could serve as potent, non-toxic, broad-range antiepileptic drugs capable of targeting both ictogenesis and epileptogenesis. A uracil QSAR model was also developed that could be used in the future to guide further analogue synthesis.