{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T10:46:58Z","timestamp":1784630818257,"version":"3.55.0"},"reference-count":37,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M691698"],"award-info":[{"award-number":["2021M691698"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973299"],"award-info":[{"award-number":["81973299"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR202111150135"],"award-info":[{"award-number":["ZR202111150135"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, <jats:italic>N,N\u2032<\/jats:italic>\u2010{4\u2010[(4\u2010fluorobenzyl) (prop\u20102\u2010yn\u20101\u2010yl)amino]\u20101,2\u2010phenylene}bis(3,3\u2010dimethylbutanamide).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010cell recordings were used to evaluate Kv7 channel openers. Site\u2010directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ\u2010induced kindling were utilized to test compound antiepileptic activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The novel compound 1025c selectively activates whole\u2010cell Kv7.2\/7.3 currents in a concentration\u2010dependent manner, with half\u2010maximal effective concentration of .91\u2009\u00b1\u2009.17\u2009\u03bcmol\u00b7L<jats:sup>\u22121<\/jats:sup>. The 1025c compound also causes a leftward shift in Kv7.2\/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (\u0394V<jats:sub>1\/2<\/jats:sub>) of \u221218.6\u2009\u00b1\u20093.0\u2009mV. Intraperitoneal administration of 1025c demonstrates dose\u2010dependent antiseizure activities in assays of MES, scPTZ, and PTZ\u2010induced kindling models. Moreover, through site\u2010directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c\u2010mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18092","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T14:35:25Z","timestamp":1723646125000},"page":"2923-2934","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity"],"prefix":"10.1111","volume":"65","author":[{"given":"Hongbin","family":"Wang","sequence":"first","affiliation":[{"name":"Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy Qingdao University Medical College  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Qiao","sequence":"additional","affiliation":[{"name":"School of Health and Life Sciences University of Health and Rehabilitation Sciences  Qingdao China"},{"name":"Qingdao Key Laboratory of Neurorehabilitation University of Health and Rehabilitation Sciences  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Luan","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy Qingdao University Medical College  Qingdao 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