Recently, the imidazolinone derivative
imepitoin has been approved for treatment of canine
epilepsy.
Imepitoin acts as a low-affinity partial agonist at the
benzodiazepine (BZD) site of the GABAA receptor and is the first compound with such mechanism that has been developed as an
antiepileptic drug (AED). This mechanism offers several advantages compared to full agonists, including less severe adverse effects and a lack of tolerance and dependence liability, which has been demonstrated in rodents, dogs, and nonhuman primates. In clinical trials in epileptic dogs,
imepitoin was shown to be an effective and safe AED. Recently,
seizures in dogs have been proposed as a translational platform for human therapeutic trials on new
epilepsy treatments. In the present study, we compared the
anticonvulsant efficacy of
imepitoin,
phenobarbital and the high-affinity partial BZD agonist
abecarnil in the timed i.v.
pentylenetetrazole (PTZ) seizure threshold test in dogs and, for comparison, in mice. Furthermore, adverse effects of treatments were compared in both species. All drugs dose-dependently increased the PTZ threshold in both species, but
anticonvulsant efficacy was higher in dogs than mice. At the doses selected for this study,
imepitoin was slightly less potent than
phenobarbital in increasing seizure threshold, but markedly more tolerable in both species. Effective doses of
imepitoin in the PTZ seizure model were in the same range as those suppressing spontaneous recurrent
seizures in epileptic dogs. The study demonstrates that low-affinity partial agonists at the
benzodiazepine site of the GABAA receptor, such as
imepitoin, offer advantages as a new category of AEDs.