Abstract Details

Title Effects of Cenobamate on GABA-A Receptor Modulation

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 6-033

Objective To investigate the effects of cenobamate on GABA_A receptors and GABA-mediated currents.

Background Cenobamate, a novel antiepileptic drug, modulates several properties of voltage-gated sodium ion channels, with preferential inhibition of the persistent current.

Design/Methods Radioligand binding displacement assays were conducted to assess the binding of cenobamate on GABA_A receptor (GABA_AR) sites. Relative activities on human GABA_AR subtypes were studied using electrophysiological analysis on six human GABA_A ion channel subtypes expressed in heterologous cells. Potentiation of GABA-induced currents, as well as effects on both phasic and tonic GABA_A currents, were assessed in rat hippocampal CA3 neurons, rat dentate gyrus granule cells (DGGCs), and mouse and rat hippocampal CA1 neurons. Electrophysiological recordings were obtained using conventional whole-cell patch clamp assays.

Results Cenobamate did not significantly displace the binding of GABA, muscimol, flunitrazepam, or Ro-15-1788 (flumazenil) to GABA_A receptors. However, cenobamate significantly displaced the binding of TBPS radioligand to GABA-gated Cl- channel (Ki=228-250 µM), consistent with its positive allosteric modulation of human GABA_A receptor subtypes (EC₅₀ range: 42-194 µM for α1β2γ2, α2β3γ2, α3β3γ2, α4β3γ2, α5β3γ2, α6β3γ2). In rat hippocampal CA3 neurons, cenobamate (≥30 µM) significantly enhanced GABA-induced current (EC₅₀=164 µM) in a concentration-dependent manner. In contrast to diazepam, the potentiation of GABA-induced currents by cenobamate was not affected by flumazenil, a selective benzodiazepine receptor antagonist. In mouse CA1 neurons, cenobamate significantly delayed the decay of evoked inhibitory postsynaptic currents without altering the peak amplitude. Cenobamate also enhanced tonic GABA_A currents in a concentration-dependent manner in rat CA1 neurons and DGGCs, although the effect was more prominent in CA1 neurons.

Conclusions Cenobamate showed non-benzodiazepine-type positive allosteric modulation of the GABA_A receptor. Enhancement of GABA_AR-mediated currents occurred in both the phasic and tonic modality in rodent hippocampal neurons. The modulation of GABA_AR-mediated currents, along with the previously shown sodium ion channel inhibition, may contribute to cenobamate’s antiepileptic activity.

Authors/Disclosures
PRESENTER	No disclosure on file
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Susan M. Melnick, PhD (SK Life Science, Inc.)	Susan M. Melnick, PhD has received personal compensation for serving as an employee of SK Life Science, Inc.. Susan M. Melnick, PhD has received intellectual property interests from a discovery or technology relating to health care.
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