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Understanding these mechanisms is essential for optimizing therapeutic efficacy and safety. Flecainide, a class Ic anti\u2010arrhythmic agent, is also used for non\u2010dystrophic myotonias but lacks use in epilepsy. This study aimed to elucidate the mechanisms underlying the isoform differences in the state\u2010dependent block of flecainide.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We employed site\u2010directed mutagenesis, electrophysiological recordings and structural modelling with docking simulations to analyse flecainide interactions with Na\n                      <jats:sub>v<\/jats:sub>\n                      1.2 (brain), Na\n                      <jats:sub>v<\/jats:sub>\n                      1.4 (skeletal muscle) and Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5 (cardiac) isoforms in the resting, open and inactivated states.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Flecainide showed the highest affinity for Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5, followed by Na\n                      <jats:sub>v<\/jats:sub>\n                      1.4 and the lowest for Na\n                      <jats:sub>v<\/jats:sub>\n                      1.2 across all states. Within each isoform, affinity ranked as inactivated\u2009&gt;\u2009open\u2009&gt;\u2009resting. In Na\n                      <jats:sub>v<\/jats:sub>\n                      1.5, alanine substitution of a phenylalanine (Phe) residue in DIV\u2010S6 caused the greatest affinity reduction, particularly in the open and inactivated states. Structural models revealed isoform\u2010 and state\u2010dependent binding poses, with the piperidine nitrogen consistently pointing towards the selectivity filter and positioned higher in the open and inactivated states. Phe in DIV\u2010S6 contributed to high\u2010affinity binding, and the distance between the aromatic ring centers of flecainide and Phe correlated with the isoform differences in high affinities and the state\u2010dependent block within each isoform.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>This study clarifies the structural basis for isoform\u2010 and state\u2010dependent drug affinities, providing insights that may guide development of isoform\u2010selective drugs with improved therapeutic profiles.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70444","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T03:01:48Z","timestamp":1776999708000},"page":"4145-4162","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Flecainide binding dynamics in voltage\u2010gated sodium channels: A comparative isoform analysis of the state\u2010dependent block"],"prefix":"10.1111","volume":"183","author":[{"given":"Tatsuo","family":"Munakata","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy at Fukuoka International University of Health and Welfare  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsuko","family":"Kumada","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy International University of Health and Welfare  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Katayama","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy International University of Health and Welfare  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy International University of Health and Welfare  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Sunami","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy International University of Health and Welfare  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.102.8.921"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16178"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.81.5.613"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.101.14.1698"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2416181122"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.049759"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0896-6273(00)81133-2"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2006.09.022"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17441"},{"key":"e_1_2_12_11_1","unstructured":"Dassault Syst\u00e8mes BIOVIA.2016Discovery Studio Visualizer Discovery Studio Modeling Environment Dassault Syst\u00e8mes San Diego CA."},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002721"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.046995"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1414-3"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220578120"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1996.76.3.887"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2011.00068"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.69.4.497"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4157(77)90003-X"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110735"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.021"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.11.041"},{"key":"e_1_2_12_23_1","first-page":"547","volume-title":"Goodman and Gilman's The Pharmacological Basis of Therapeutics","author":"Knollmann B. 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