Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil
Open accessAbstract
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.
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Padsevonil and related ligands extend this pharmacology with optimized SV2A engagement and limited drug interaction profiles.
“Padsevonil and related ligands extend this pharmacology with optimized SV2A engagement and limited drug interaction profiles, positioning the class for chronic adjunctive use where synaptic resilience and clean tolerability are essential [175,219,220].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [220]
The padsevonil discovery and mechanism section (page unavailable) describes its rational design and substantially higher SV2A affinity than levetiracetam or brivaracetam. The pharmacokinetics and adverse-effects section (page unavailable) does not establish a limited drug-interaction profile for padsevonil. The review also reports that padsevonil’s development stopped after its phase III trial failed to meet its primary endpoints, so it does not support positioning padsevonil for chronic adjunctive use. (LLM, conf=0.87)
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References 150 · Cited by 35
Research works printed but not linked: 2
- [5]5. Devinsky O, Vezzani A, O'Brien TJ, Jette N, Scheffer IE, de Curtis M, et al. Epilepsy. Nat Rev Dis Primers 2018, 4: 18024.
- [106]106. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted of is solely governed the terms of such publishing agreement and applicable law.
- Authors
- Wu, P.-P., Cao, B.-R., Tian, F.-Y., & Gao, Z.-B.
- Affiliations
- Chinese Academy of Sciences (CN)
- Venue
- Neuroscience Bulletin
- Published
- 2023-10-28
- Volume
- 40
- Issue
- 5
- Pages
- 594-608
- ISSN
- 1995-8218 (ISSN-L)
- 1673-7067
- PMC
- PMC11127901
- OpenAlex
- W4388007412
- Cited by
- 35
- References
- 150
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 8
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neuroscience Bulletin (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- epilepsy, antiepileptic drugs, SV2A, levetiracetam, brivaracetam, drug development, drug-resistant epilepsy, drug-drug interactions, structure-activity relationship
- MeSH terms
- Levetiracetam, Animals, Anticonvulsants, Epilepsy, Humans, Ligands, Membrane Glycoproteins, Nerve Tissue Proteins, Pyrrolidinones
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