{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:47:18Z","timestamp":1792133238842,"version":"4.4.0"},"reference-count":14,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp;amp; Perspec"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Central nervous system (CNS) liabilities remain a significant cause of attrition during small molecule drug development. We previously developed the in\u00a0vitro seizure liability assay (iLA\n                    <jats:sup>seizure<\/jats:sup>\n                    ), a new approach methodology (NAM) comprising a human induced pluripotent stem cell neuron microelectrode array (MEA) assay coupled with a panel of human ion channels associated with CNS perturbation and especially seizure, evaluated by electrophysiology. Here, we present a series of illustrative case studies demonstrating the potential applications of iLA\n                    <jats:sup>seizure<\/jats:sup>\n                    . Amoxapine (shows clinical seizures) gave concentration\u2010dependent changes in MEA parameters and inhibited seizure\u2010related ion channels with high potency (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009&lt;\u200930\u2009\u03bcM) at the human therapeutic concentration range (0.57\u20131.91\u2009\u03bcM). Comparison of seizure risk in five compounds in a lead series showed clear ranking, with no changes in any of the MEA parameters for one of the five compounds. In a second case study, there were dog\u2010specific seizures in good laboratory practice (GLP) toxicology: this was explained by a clear seizurogenic phenotype at 100\u2009\u03bcM in MEA for a dog\u2010specific metabolite and a hit on the ion channel panel at NMDA1\/2A with high potency (IC\n                    <jats:sub>50<\/jats:sub>\n                    of 19.3\u2009\u03bcM). In the third case study, one clinical candidate showed no changes in MEA parameters at the clinical C\n                    <jats:sub>max<\/jats:sub>\n                    of 1\u2009\u03bcM, whereas the other clinical candidate showed a potent seizurogenic phenotype with changes in many MEA parameters at 3\u201310\u2009\u03bcM, correlating with the clinical C\n                    <jats:sub>max<\/jats:sub>\n                    of 5\u2009\u03bcM. Overall, iLA\n                    <jats:sup>seizure<\/jats:sup>\n                    offers new opportunities to predict, understand, and avoid CNS side effects such as seizures in drug discovery and development, before animals, resources, and time have been wasted. This work should be considered within the context of recent proposed updates to safety pharmacology guidelines, such as ICH S7A. However, further work is needed to validate assay performance and clarify the context of use.\n                  <\/jats:p>","DOI":"10.1002\/prp2.70317","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:44:52Z","timestamp":1788878692000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Implementation of the In\u00a0Vitro Seizure Liability Assay (\n                    <scp>\n                      iLA\n                      <sup>seizure<\/sup>\n                    <\/scp>\n                    ) in Drug Discovery and Development: Mechanism of Action Case Studies"],"prefix":"10.1002","volume":"14","author":[{"given":"Kimberly","family":"Rockley","sequence":"first","affiliation":[{"name":"ApconiX  Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7763-7558","authenticated-orcid":false,"given":"Ruth","family":"Roberts","sequence":"additional","affiliation":[{"name":"ApconiX  Macclesfield UK"},{"name":"Department of Biosciences University of Birmingham  Edgbaston UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0686-3694","authenticated-orcid":false,"given":"Hannah","family":"Jennings","sequence":"additional","affiliation":[{"name":"ApconiX  Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Jones","sequence":"additional","affiliation":[{"name":"ApconiX  Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali\u2010Anne","family":"Maizi\u00e8res","sequence":"additional","affiliation":[{"name":"ApconiX  Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Morton","sequence":"additional","affiliation":[{"name":"ApconiX  Macclesfield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4309"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2016.06.001"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","unstructured":"A. L.Walker S. Z.Imam andR. A.Roberts \u201cMinireview Drug Discovery and Development: Biomarkers of Neurotoxicity and Neurodegeneration \u201d(2018) https:\/\/doi.org\/10.1177\/1535370218801309.","DOI":"10.1177\/1535370218801309"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2009.06.003"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2019.04.005"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2007.04.008"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2008.01.004"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfad087"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00846-5"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2020.106900"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2009.11.005"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2023.105345"},{"key":"e_1_2_12_14_1","doi-asserted-by":"crossref","unstructured":"L.Zolkiewski K. L.Rockley R. A.Roberts et\u00a0al. \u201cBuilding Structure\u2010Activity Relationships (SAR) to Avoid Toxicity Due to Unwanted CNS Ion Channel Activity \u201d(2026).","DOI":"10.1093\/toxsci\/kfag094"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2026.106096"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70317","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.70317","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70317","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:15:19Z","timestamp":1792131319000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.70317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":14,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/prp2.70317"],"URL":"https:\/\/doi.org\/10.1002\/prp2.70317","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]},"assertion":[{"value":"2026-05-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70317"}}