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Review
. 2024 May;40(5):594-608.
doi: 10.1007/s12264-023-01138-2. Epub 2023 Oct 28.

Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil

Peng-Peng Wu #  1   2 , Bi-Rong Cao #  1   2 , Fu-Yun Tian #  3   4 , Zhao-Bing Gao  5   6   7
Affiliations
Review

Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil

Peng-Peng Wu et al. Neurosci Bull. 2024 May.

Abstract

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications (ASMs). Although dozens of ASMs are available in the clinic, approximately 30% of epileptic patients have medically refractory seizures; other limitations in most traditional ASMs include poor tolerability and drug-drug interactions. Therefore, there is an urgent need to develop alternative ASMs. Levetiracetam (LEV) is a first-line ASM that is well tolerated, has promising efficacy, and has little drug-drug interaction. Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein (SV) 2A, the molecular basis of its action remains unknown. Even so, the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success. This review highlights the research and development (R&D) process of LEV and its analogs, brivaracetam and padsevonil, to provide ideas and experience for the R&D of novel ASMs.

Keywords: Antiseizure medications; Brivaracetam; Epilepsy; Levetiracetam; Padsevonil; Synaptic vesicle protein 2A.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the review
Fig. 2
Fig. 2
Putative mode of action and the topology of SV2A. Left, localized at both excitatory and inhibitory synapses, SV2A may modulate synaptic transmission via multiple mechanisms, e.g., by regulating the readily releasable pool size or by participating in a pre-fusion maturation step during vesicular exocytosis as a target for residual calcium. Right, SV2A is a 12-transmembrane protein. Pathogenic mutant residues L174 and R383, glycosylation sites in a long intravesicular loop, and a putative binding site in the N terminus for synaptotagmin.
Fig. 3
Fig. 3
The chemical structures and the year of publication of piracetam, levetiracetam, brivaracetam, seletracetam and padsevonil.
See this image and copyright information in PMC

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