Design, Synthesis, and Evaluation of Novel Benzo[d]isoxazole Derivatives as Anticonvulsants by Selectively Blocking the Voltage-Gated Sodium Channel Na(V)1.1

Sodium channel blockers are important antiseizure drugs. Since the launch of phenobarbital in 1912, it has a development history of nearly 100 years. However, because of the confounding symptoms, complications, and complex intrinsic pathogenesis of epilepsy, the design and development of blockers specifically targeting sodium channels as antiseizure drugs are difficult and rarely reported. In this study, we designed and synthesized a series of novel benzo[d]isoxazole derivatives as anticonvulsants. Among them, the most potent Z-6b displayed high protection against the MES-induced seizures with an ED50 value of 20.5 mg/kg and a high protective index (TD50/ED50) of 10.3. In addition, Z-6b significantly inhibited Na(V)1.1 channels in patch-clamp experiments but almost did not inhibit Na(V)1.2, Na(V)1.3, and Na(V)1.6 channels. These findings strongly support the hypothesis that new benzo[d]isoxazole derivatives display anticonvulsant activity by selectively blocking voltage-gated sodium channel Na(V)1.1, which provides good alternatives for developing selective Na(V)1.1 channel blockers as antiseizure drugs in the future.