{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:52:23Z","timestamp":1771930343741,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T00:00:00Z","timestamp":1684368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>As of 2022, 36 anti\u2010seizure 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 \u03b3\u2010aminobutyric acid (GABA) transporter 1 (GAT1). Here, we describe the preclinical characteristics of E2730.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Anti\u2010seizure effects of E2730 were evaluated in several animal models of epilepsy: corneal kindling, 6\u2009Hz\u201344\u2009mA 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 [<jats:sup>3<\/jats:sup>H]E2730 binding assay. The GAT1\u2010selectivity over other GABA transporters was examined by GABA uptake assay of GAT1, GAT2, GAT3, or betaine\/GABA transporter 1 (BGT\u20101) stably expressing HEK293 cells. To further investigate the mechanism for E2730\u2010mediated inhibition of GAT1, in vivo microdialysis and in vitro GABA uptake assays were conducted under conditions of different GABA concentrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>E2730 showed anti\u2010seizure effects in the assessed animal models with an approximately &gt;20\u2010\u200dfold margin between efficacy and motor incoordination. [<jats:sup>3<\/jats:sup>H]E2730 binding on brain synaptosomal membrane was abolished in GAT1\u2010deficient mice, and E2730 selectively inhibited GAT1\u2010mediated GABA uptake over other GABA transporters. In addition, results of GABA uptake assays showed that E2730\u2010mediated inhibition of GAT1 positively correlated to the level of ambient GABA in vitro. E2730 also increased extracellular GABA concentration in hyperactivated conditions but not under basal levels in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12741","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T11:21:00Z","timestamp":1681384860000},"page":"834-845","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Discovery of<scp>E2730<\/scp>, a novel selective uncompetitive<scp>GAT1<\/scp>inhibitor, as a candidate for anti\u2010seizure medication"],"prefix":"10.1002","volume":"8","author":[{"given":"Kazuyuki","family":"Fukushima","sequence":"first","affiliation":[{"name":"Deep Human Biology Learning Eisai Co., Ltd. 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Tsukuba Ibaraki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delia M.","family":"Talos","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeri","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas S.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances E.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahisa","family":"Hanada","sequence":"additional","affiliation":[{"name":"Deep Human Biology Learning Eisai Co., Ltd. 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