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

Abstract

Summary Objective Brivaracetam ( BRV ) and levetiracetam ( LEV ) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A ( SV 2A) 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 SV 2A protein, which is not apparent in radioligand‐binding competition studies. In this study, we used a recently identified SV 2A allosteric modulator, UCB 1244283, that appears to induce conformational changes in SV 2A, 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 SV 2A 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 SV 2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV 2A protein.