Effects of Cenobamate on GABA-A Receptor Modulation (P1.5-033)

Objective: To investigate the effects of cenobamate on GABAA 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 GABAA receptor (GABAAR) sites. Relative activities on human GABAAR subtypes were studied using electrophysiological analysis on six human GABAA ion channel subtypes expressed in heterologous cells. Potentiation of GABA-induced currents, as well as effects on both phasic and tonic GABAA 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 GABAA 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 GABAA 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 GABAA 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 GABAA receptor. Enhancement of GABAAR-mediated currents occurred in both the phasic and tonic modality in rodent hippocampal neurons. The modulation of GABAAR-mediated currents, along with the previously shown sodium ion channel inhibition, may contribute to cenobamate’s antiepileptic activity. Disclosure: Dr. Sharma has nothing to disclose. Dr. Song has nothing to disclose. Dr. Nakamura has nothing to disclose. Dr. Neupane has nothing to disclose. Dr. Shin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SK Biopharmaceuticals Co., Ltd. Dr. Melnick has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SK Life Science, Inc. Dr. Glenn has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SK Life Science, Inc. Dr. Jang has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Park has nothing to disclose.