{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:28:42Z","timestamp":1788571722480,"version":"build-2803163510"},"reference-count":53,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T00:00:00Z","timestamp":1741996800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      \u03b3\u2010Aminobutyric acid type A (GABA\n                      <jats:sub>A<\/jats:sub>\n                      ) receptor positive allosteric modulators (PAMs) that lack \u03b1\u2010subunit selectivity, including benzodiazepines such as diazepam, exhibit antiseizure actions in animal models and in humans. ENX\u2010101 is a deuterated analog of the \u237a2,3,5\u2010selective GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor PAM L\u2010838,417. The purpose of this study was to characterize the \u03b1\u2010subunit selectivity of ENX\u2010101 and evaluate its antiseizure potential in preclinical seizure and epilepsy models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      ENX\u2010101 potentiation of GABA chloride current responses in cells expressing recombinant GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors were evaluated using an automated patch clamp assay. Antiseizure effects of ENX\u2010101 were examined in the mouse 6\u2009Hz test at 32 and 44\u2009mA, amygdala kindled rats, and Genetic Absence Epilepsy Rat from Strasbourg (GAERS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ENX\u2010101 displayed partial PAM activity with respect to diazepam at GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors containing \u03b12, \u03b13, or \u03b15 subunits but did not enhance GABA responses of GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors containing \u03b11 subunits. ENX\u2010101 (30, 100, and 300\u2009mg\/kg, i.p.) and diazepam protected most animals in the 6\u2009Hz model at 32\u2009mA but was less effective at 44\u2009mA. In amygdala kindled rats, ENX\u2010101 (1\u2013100\u2009mg\/kg, p.o.) reduced behavioral seizure severity and afterdischarge duration in a dose\u2010dependent manner. ENX\u2010101 (0.075\u2013100\u2009mg\/kg, p.o.) caused dose\u2010dependent, persistent (&gt;130\u2009min) inhibition of spontaneous spike\u2010and\u2010wave discharges (SWDs) in GAERS, whereas diazepam transiently inhibited discharges. ENX\u2010101 did not cause motor impairment, as measured by performance in the rotarod assay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      ENX\u2010101 is an \u03b12,\u03b13,\u03b15\u2010selective GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor PAM that has high potency and partial efficacy. The drug is highly effective in rodent seizure and epilepsy models. ENX\u2010101 is most potent in the GAERS model of absence epilepsy, and active in the 6\u2009Hz model and amygdala kindled rats. These results demonstrate that a partial, subtype\u2010selective GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor PAM has activity in translationally validated preclinical epilepsy screening models. Clinical evaluation of ENX\u2010101 as a treatment for focal and generalized epilepsies is warranted.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18340","type":"journal-article","created":{"date-parts":[[2025,3,15]],"date-time":"2025-03-15T09:59:36Z","timestamp":1742032776000},"page":"2124-2136","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>ENX<\/scp>\n                    \u2010101, a\n                    <scp>\n                      GABA\n                      <sub>A<\/sub>\n                    <\/scp>\n                    receptor \u03b12,3,5\u2010selective positive allosteric modulator, displays antiseizure effects in rodent seizure and epilepsy models"],"prefix":"10.1111","volume":"66","author":[{"given":"Jordi","family":"Serrats","sequence":"first","affiliation":[{"name":"Engrail Therapeutics  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3455-0209","authenticated-orcid":false,"given":"Krishna C.","family":"Vadodaria","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Brubaker","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8175-0553","authenticated-orcid":false,"given":"Melissa","family":"Barker\u2010Haliski","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Center for Epilepsy Drug Discovery, School of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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