Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Abstract

Objective: Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV.

Methods: Radioligand binding studies were carried out using [³ H]BRV and [³ H]LEV. Studies were performed in membranes from both recombinant cells expressing human SV2A protein and human brain tissue.

Results: The modulator increased the binding of both radioligands but by different mechanisms. For [³ H]BRV, the increase was driven mainly by an increase in affinity, whereas for [³ H]LEV, the increase was due to an increase in the number of apparent binding sites. Kinetic studies confirmed this differential effect.

Significance: These studies suggest that LEV and BRV may act at different binding sites or interact with different conformational states of the SV2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV2A protein.

Keywords: Antiepileptic drug; Epilepsy; Modulator; Synaptic vesicle protein.