BAER‐101, a selective potentiator of α2‐ and α3‐containing GABAA receptors, fully suppresses spontaneous cortical spike‐wave discharges in Genetic Absence Epilepsy Rats from Strasbourg (GAERS)

Abstract

AbstractBAER‐101 (formerly AZD7325) is a selective partial potentiator of α2/3‐containing γ‐amino‐butyric acid A receptors (GABAARs) and produces minimal sedation and dizziness. Antiseizure effects in models of Dravet and Fragile X Syndromes have been published. BAER‐101 has been administered to over 700 healthy human volunteers and patients where it was found to be safe and well tolerated. To test the extent of the antiseizure activity of BAER‐1010, we tested BAER‐101 in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model, a widely used and translationally relevant model. GAERS rats with recording electrodes bilaterally located over the frontal and parietal cortices were used. Electroencepholographic (EEG) signals in freely moving awake rats were analyzed for spike‐wave discharges (SWDs). BAER‐101 was administered orally at doses of 0.3–100 mg/kg and diazepam was used as a positive control using a cross‐over protocol with a wash‐out period between treatments. The number of SWDs was dose‐dependently reduced by BAER‐101 with 0.3 mg/kg being the minimally effective dose (MED). The duration of and total time in SWDs were also reduced by BAER‐101. Concentrations of drug in plasma achieved an MED of 10.1 nM, exceeding the Ki for α2 or α3, but 23 times lower than the Ki for α5‐GABAARs. No adverse events were observed up to a dose 300× MED. The data support the possibility of antiseizure efficacy without the side effects associated with other GABAAR subtypes. This is the first report of an α2/3‐selective GABA PAM suppressing seizures in the GAERS model. The data encourage proceeding to test BAER‐101 in patients with epilepsy.