Cenobamate is a novel
antiepileptic drug under investigation for use in patients with focal (partial-onset)
seizures. To understand its potential molecular mechanism of action, the effects of
cenobamate on GABAA-mediated currents and GABAA receptors in rodent hippocampal neurons were examined.
Cenobamate potentiated
GABA-induced currents (IGABA) in acutely isolated CA3 pyramidal cells in a concentration-dependent manner (EC50, 164 μM), which was not affected by
flumazenil, a
benzodiazepine receptor antagonist.
Cenobamate enhanced tonic GABAA currents (Itonic), which is defined as a holding current shift by the GABAA receptor antagonist
bicuculline (EC50, 36.63 μM). At therapeutically relevant concentrations,
cenobamate induced minimal changes in the frequency, amplitudes, and decay time of spontaneous inhibitory postsynaptic currents in the CA1 neurons.
Flumazenil failed to affect
cenobamate-potentiated Itonic and Iphasic in CA1 neurons.
Cenobamate showed positive allosteric modulation of
GABA-induced IGABA mediated by GABAA receptors. This effect was similar for all tested hGABAA receptors containing six different alpha subunits (α1β2γ2 or α2-6β3γ2), with EC50 values ranging from 42 to 194 μM.
Cenobamate did not displace the binding of
flunitrazepam, a
benzodiazepine derivative, or
flumazenil to GABAA receptors. The results showed that
cenobamate, a novel
antiepileptic drug, acts as a positive allosteric modulator of high-affinity GABAA receptors, activated by
GABA at a site independent of the
benzodiazepine binding site and efficiently enhances Itonic inhibition in hippocampal neurons, which could be an underlying molecular mechanism stabilizing neural circuits of the epileptic hippocampus.