Although
benzodiazepines (BZDs) offer a wide spectrum of
antiepileptic activity against diverse types of epileptic
seizures, their use in the treatment of
epilepsy is limited because of adverse effects, loss of efficacy (tolerance), and development of physical and psychological dependence. BZDs act as positive allosteric modulators of the inhibitory
neurotransmitter GABA by binding to the BZD recognition site ("BZD receptor") of the GABAA receptor. Traditional BZDs such as
diazepam or
clonazepam act as full agonists at this site, so that one strategy to resolve the disadvantages of these compounds would be the development of partial agonists with lower intrinsic efficacy at the BZD site of the GABAA receptor. Several BZD site partial or subtype selective compounds, including
bretazenil,
abecarnil, or
alpidem, have been developed as anxioselective
anxiolytic drugs, but
epilepsy was not a target indication for such compounds. More recently, the
imidazolone derivatives
imepitoin (
ELB138) and
ELB139 were shown to act as low-affinity partial agonists at the BZD site of the GABAA receptor, and
imepitoin was developed for the treatment of
epilepsy.
Imepitoin displayed a broad spectrum of
anticonvulsant activity in diverse seizure and
epilepsy models at tolerable doses, and, as expected from its mechanism of action, lacked tolerance and abuse liability in rodent and primate models. The more favorable pharmacokinetic profile of
imepitoin in dogs versus humans led to the decision to develop
imepitoin for the treatment of canine
epilepsy. Based on randomized controlled trials that demonstrated
antiepileptic efficacy and high tolerability and safety in epileptic dogs, the
drug was recently approved for this indication in Europe. Hopefully, the favorable profile of
imepitoin for the treatment of
epilepsy in dogs will reactivate the interest in partial BZD site agonists as new treatments for human
epilepsy.