| Epilepsy is a common neurological disorder that affects approximately 1-2% of the population. Treatment of epilepsy focuses on the suppression of seizures via the use of antiepileptic drugs (AEDs). Recent advances in the treatment of epilepsy have produced several new AEDs. However, despite the availability of newer AEDs, one-third of epilepsy patients continue to suffer from uncontrolled seizures. In addition, substantial problems exist with toxicity, resistance, and idiosyncratic reactions for several AEDs, all of which likely contribute to their failure rate. Subsequently, a significant achievement would be to not only identify effective and safer AEDs, but also elucidate the mechanism by which these aims are accomplished. Voltage-gated sodium (Na) channels play a critical role in determining neuronal excitability and constitute a proven target for the suppression of seizures.; This thesis examines the biophysical and behavioral properties of a set of rationally designed small molecule inhibitors of neuronal voltage-gated Na channels. The central hypothesis of this dissertation proposes that using traditional medicinal chemistry modifications of the alpha-hydroxyamide scaffold, novel Na channel blockers can be designed, and their mechanisms of inhibition evaluated using patch-clamp electrophysiology. Furthermore, the biophysical properties of these novel compounds could be predictive of their in vivo AED activity. In this thesis, we have designed and synthesized novel Na channel blockers, and determined their biophysical effects on recorded neuronal Na currents. Each lead compound, JDA3135, HS357, and YWI92 exhibited a greater affinity for the inactivated state of the Na channel over the resting state of the channel. In addition, each of these compounds demonstrated greater use-dependent block and delayed recovery from inactivation, in comparison to their respective parent compounds. These state-dependent properties were corroborated with a selective reduction of neuronal excitability in hyperexcited CA1 hippocampal neurons. Consistent with these electrophysiology studies, each lead compound protected from seizure activity induced in acute and/or chronic models of epilepsy. Efficacious doses of JDA3135, HS357, and YW192 were without effect on motor coordination, as assessed in the rotorod toxicity assay. Thus, the a-hydroxyamide scaffold represents an important structural motif from which effective and safer anticonvulsants may be developed. |
