title: The pharmacology of imepitoin: the first partial benzodiazepine receptor agonist developed for the treatment of epilepsy.
abstract: 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.
authors.affiliation: Drug-Consult.Net, 39108, Magdeburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Rundfeldt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004285:Dogs; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D058785:GABA-A Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism
chemical_list: C116306:AWD 131-138; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines