{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:16:04Z","timestamp":1785244564014,"version":"3.55.0"},"reference-count":27,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GRK 2515"],"award-info":[{"award-number":["GRK 2515"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The voltage\u2010gated potassium channel K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 (KCNQ1) is essential for cardiac repolarization. Loss\u2010of\u2010function mutations prolong the action potential and cause long QT syndrome 1, predisposing to malignant arrhythmias. Pharmacological activators of K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 are therefore of therapeutic interest. Among them, the 1,4\u2010benzodiazepine derivative (R)\u2010L3 is a potent activator that not only increases current amplitude but also slows activation and deactivation kinetics and abolishes inactivation by uncoupling the voltage sensor from the pore. To explore the structure\u2013activity relationships (SAR) of (R)\u2010L3, we synthesized and functionally characterized a series of novel 1,4\u2010benzodiazepine derivatives and examined their effects on K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 gating. Human K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 channels were heterologously expressed in\n                    <jats:italic>Xenopus laevis<\/jats:italic>\n                    oocytes. Two\u2010electrode voltage clamp recordings were performed to assess current amplitude and kinetic parameters of activation, deactivation, and inactivation. 1,4\u2010Benzodiazepines modified at 1\u2010position reproduced the canonical effects of (R)\u2010L3, including increased current amplitude and suppression of inactivation to varying degrees. Some derivatives displayed completely altered profiles: Modulation of activation, altered (de\u2010)activation kinetics or exerting attenuated effects on inactivation could be uncoupled. These differences suggest that modifications of the 1,4\u2010benzodiazepine scaffold at 1\u2010position shift the interaction between pore binding and voltage sensor\u2013pore uncoupling to isolate kinetic effects. Our data demonstrates that (R)\u2010L3 analogues can differentially modulate K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 gating. By identifying structural determinants of efficacy, this study provides a framework for rational design of next\u2010generation K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 activators. Such compounds may serve as pharmacological tools for dissecting electromechanical coupling in K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 and hold promise as candidates for antiarrhythmic therapy in long QT syndrome.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70305","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:35:16Z","timestamp":1783920916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Electro\u2010Mechanical Uncoupling of K\n                    <sub>V<\/sub>\n                    7.1 Voltage Sensor and Pore by 1,4\u2010Benzodiazepines Is Modulated by Decoration of Position 1"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9117-4314","authenticated-orcid":false,"given":"Florian","family":"Ro\u00dfner","sequence":"first","affiliation":[{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Universit\u00e4t M\u00fcnster M\u00fcnster Germany"},{"name":"Institute of Pharmaceutical and Medicinal Chemistry University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-714X","authenticated-orcid":false,"given":"Thomas","family":"Jepps","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo Hjorth","family":"Bentzen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Strutz\u2010Seebohm","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH) University Hospital M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9030-8417","authenticated-orcid":false,"given":"Bernhard","family":"W\u00fcnsch","sequence":"additional","affiliation":[{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Universit\u00e4t M\u00fcnster M\u00fcnster Germany"},{"name":"Institute of Pharmaceutical and Medicinal Chemistry University of M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9303-5373","authenticated-orcid":false,"given":"Guiscard","family":"Seebohm","sequence":"additional","affiliation":[{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Universit\u00e4t M\u00fcnster M\u00fcnster Germany"},{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH) University Hospital M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/384078a0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/384080a0"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00002.2005"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811897106"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1159\/000329965"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2017.06.005"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300684110"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2012.00142"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201582109"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00243-4"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0196-17"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.68.1.77"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-16-4254-8_15"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.54.1.220"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.080887"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.124.325009"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(25)09808-6"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802426200"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000102866.67863.2B"},{"key":"e_1_2_8_21_1","first-page":"1","article-title":"Two 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