{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:30:04Z","timestamp":1790325004406,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T00:00:00Z","timestamp":1586995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015661","name":"UCB Pharma","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015661","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets: synaptic vesicle 2 proteins and \u03b3\u2010aminobutyric acid type A receptors (GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs), respectively. Functional aspects of padsevonil at the postsynaptic target, GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs, were characterized in experiments reported here.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The effect of padsevonil on GABA\u2010mediated Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      currents was determined by patch clamp on recombinant human GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs (\u03b11\u03b22\u03b32) stably expressed in a CHO\u2010K1 cell line and on native GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs in cultured rat primary cortical neurons. Padsevonil selectivity for GABA\n                      <jats:sub>A<\/jats:sub>\n                      R subtypes was evaluated using a two\u2010electrode voltage clamp on recombinant human GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs (\u03b11\u20105\/\u03b22\/\u03b32) in\n                      <jats:italic>Xenopus<\/jats:italic>\n                      oocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In recombinant GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs, padsevonil did not evoke Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      currents in the absence of the agonist GABA. However, when co\u2010administered with GABA at effective\u00a0concentration (EC)\n                      <jats:sub>20<\/jats:sub>\n                      , padsevonil potentiated GABA responses by 167% (EC\n                      <jats:sub>50<\/jats:sub>\n                      138\u00a0nmol\/L) and demonstrated a relative efficacy of 41% compared with zolpidem, a reference benzodiazepine site agonist. Similarly, padsevonil demonstrated GABA\u2010potentiating activity at native GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs (EC\n                      <jats:sub>50<\/jats:sub>\n                      208\u00a0nmol\/L) in cultured rat cortical neurons. Padsevonil also potentiated GABA (EC\n                      <jats:sub>20<\/jats:sub>\n                      ) responses in GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs expressed in oocytes, with higher potency at \u03b11\u2010 and \u03b15\u2010containing receptors (EC\n                      <jats:sub>50<\/jats:sub>\n                      295 and 281\u00a0nmol\/L) than at \u03b12\u2010 and \u03b13\u2010containing receptors (EC\n                      <jats:sub>50<\/jats:sub>\n                      1737 and 2089\u00a0nmol\/L). Compared with chlordiazepoxide\u2014a nonselective, full GABA\n                      <jats:sub>A<\/jats:sub>\n                      R agonist\u2014the relative efficacy of padsevonil was 60% for \u03b11\u03b22\u03b32, 26% for \u03b12\u03b22\u03b32, 56% for \u03b13\u03b22\u03b32, and 41% for \u03b15\u03b22\u03b32; no activity was observed at benzodiazepine\u2010insensitive \u03b14\u03b22\u03b32 receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      Results of functional investigations on recombinant and native neuronal GABA\n                      <jats:sub>A<\/jats:sub>\n                      Rs show that padsevonil acts as a positive allosteric modulator of these receptors, with a partial agonist profile at the benzodiazepine site. These properties may confer better tolerability and lower potential for tolerance development compared with classic benzodiazepines currently used in the clinic.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.16497","type":"journal-article","created":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T08:29:21Z","timestamp":1587025761000},"page":"914-923","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Functional characterization of the antiepileptic drug candidate, padsevonil, on GABA\n                    <sub>A<\/sub>\n                    receptors"],"prefix":"10.1111","volume":"61","author":[{"given":"Isabelle","family":"Niespodziany","sequence":"first","affiliation":[{"name":"Neurosciences Therapeutic Area UCB Pharma Braine l\u2019Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Ghisdal","sequence":"additional","affiliation":[{"name":"Neurosciences Therapeutic Area UCB Pharma Braine l\u2019Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Mullier","sequence":"additional","affiliation":[{"name":"Neurosciences Therapeutic Area UCB Pharma Braine l\u2019Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyn","family":"Wood","sequence":"additional","affiliation":[{"name":"Neurosciences Therapeutic Area UCB Pharma Braine l\u2019Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Provins","sequence":"additional","affiliation":[{"name":"Neurosciences Therapeutic Area UCB Pharma Braine l\u2019Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal M.","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Neurosciences Therapeutic Area UCB Pharma Braine l\u2019Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-7151","authenticated-orcid":false,"given":"Christian","family":"Wolff","sequence":"additional","affiliation":[{"name":"Neurosciences Therapeutic Area UCB Pharma Braine l\u2019Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01713.x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.261149"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12192"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13638"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12347"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/1087057113501555"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.089920"},{"key":"e_1_2_9_9_1","first-page":"1364","article-title":"Pharmacology of the human gamma\u2010aminobutyric acidA receptor alpha 4 subunit expressed in Xenopus laevis oocytes","volume":"50","author":"Whittemore ER","year":"1996","journal-title":"Mol Pharmacol"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2018.03.006"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.386664"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2017.03.003"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.01.036"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-013-0129-z"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3502"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.108.00505"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1625"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(91)81076-K"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)45961-3"},{"key":"e_1_2_9_20_1","first-page":"670","article-title":"Functional characterization of human \u03b3\u2010aminobutyric acid A receptors containing the \u03b14 subunit","volume":"50","author":"Wafford KA","year":"1996","journal-title":"Mol Pharmacol"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.07.002"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.239590"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.261222"},{"key":"e_1_2_9_24_1","first-page":"693","article-title":"Anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. 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