Discovery of 2-Ethynylisoborneol as a Highly Potent Anti-seizure Agent

Epilepsy is a type of severe neurological disorder that is caused by abnormal neuronal discharges. Natural D-(+)-borneol has been proven to attenuate epileptic seizures, while its potency and pharmacokinetic profiles remain improved. In this study, optimization strategies including prodrug modification, bioisosterism, and metabolic site blocking were performed for aiming to hunt more potent antiseizure borneol derivatives. Thus, various D-(+)-borneol derivatives were prepared and subjected to in vivo antiseizure evaluation with PTZ and MES models. And compound 13 was identified as a promising candidate with favorable pharmacokinetic properties (F = 114.8%) coupled with high and broad-spectrum antiseizure potential. 13 could prolong the latency to stage 6 of the PTZ model from 285.3 to 786.5 s upon oral administration of 30 mg/kg. Mechanistically, 13 was found to ameliorate epileptic seizures via weakening the excitability of glutamatergic transmission. Overall, this work provides a new optimization strategy of borneol and a new chemical entity for epilepsy treatment.