Discovery of E2730, a novel selective uncompetitive GAT1 inhibitor, as a candidate for anti-seizure medication.
GABA transporters
GAT1
anti-seizure medications
uncompetitive inhibition
Journal
Epilepsia open
ISSN: 2470-9239
Titre abrégé: Epilepsia Open
Pays: United States
ID NLM: 101692036
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
12
12
2022
accepted:
08
04
2023
medline:
4
9
2023
pubmed:
14
4
2023
entrez:
13
4
2023
Statut:
ppublish
Résumé
As of 2022, 36 anti-seizure medications (ASMs) have been licensed for the treatment of epilepsy, however, adverse effects (AEs) are commonly reported. Therefore, ASMs with a wide margin between therapeutic effects and AEs are preferred over ASMs that are associated with a narrow margin between efficacy and risk of AEs. E2730 was discovered using in vivo phenotypic screening and characterized as an uncompetitive, yet selective, inhibitor of γ-aminobutyric acid (GABA) transporter 1 (GAT1). Here, we describe the preclinical characteristics of E2730. Anti-seizure effects of E2730 were evaluated in several animal models of epilepsy: corneal kindling, 6 Hz-44 mA psychomotor seizure, amygdala kindling, Fragile X syndrome, and Dravet syndrome models. Effects of E2730 on motor coordination were assessed in accelerating rotarod tests. The mechanism of action of E2730 was explored by [ E2730 showed anti-seizure effects in the assessed animal models with an approximately >20-fold margin between efficacy and motor incoordination. [ E2730 is a novel, selective, uncompetitive GAT1 inhibitor, which acts selectively under the condition of increasing synaptic activity, contributing to a wide margin between therapeutic effect and motor incoordination.
Identifiants
pubmed: 37052238
doi: 10.1002/epi4.12741
pmc: PMC10472371
doi:
Substances chimiques
GABA Plasma Membrane Transport Proteins
0
gamma-Aminobutyric Acid
56-12-2
Anticonvulsants
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
834-845Informations de copyright
© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
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