Exploration of the mechanism of action of cenobamate

Antiseizure medications have varied effects on neurotransmitter receptors and ion channels in the brain, yet how these mechanisms of action (MoAs) translate to clinical efficacy is not well understood. Cenobamate, a tetrazole alkyl carbamate antiseizure medication (ASM), has a dual MoA: preferential inhibition of the persistent sodium current (I_NaP) while sparing the transient sodium current (I_NaT), combined with extrasynaptic tonic inhibition mediated by positive allosteric modulation of gamma-aminobutyric acid type A (GABA_A) receptors. In preclinical studies, cenobamate demonstrated broad-spectrum activity across various animal models of focal and generalized seizures. In clinical trials, cenobamate demonstrated rates of seizure freedom not observed with other voltage-gated sodium channel blockers (SCBs), whose main MoA involves modulating I_NaT or GABA_A. In addition, real-world evidence suggests cenobamate may have efficacy in adult Dravet syndrome, a loss-of-function sodium channelopathy typically aggravated by SCBs. Cenobamate's selectivity for I_NaP occurs at therapeutic concentrations, a characteristic seemingly unique among ASMs. Moreover, cenobamate preferentially modulates tonic (extrasynaptic) currents over phasic (synaptic) GABA_A currents. These combined mechanistic effects may represent an emerging class of ASMs and could explain cenobamate's broad-spectrum effect in animal seizure models and its efficacy for focal seizures in humans. In this review, we examine how cenobamate interacts with sodium currents and GABA receptor physiology and review cenobamate's efficacy profile in humans. Finally, we will postulate how specific aspects of cenobamate's dual MoA may contribute to its efficacy in comparison to other ASMs with similar MoAs.