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.