{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T22:47:53Z","timestamp":1775602073354,"version":"3.50.1"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2016,4]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Ventricular arrhythmias as a result of unintentional blockade of the K\n              <jats:sub>v<\/jats:sub>\n              11.1 (hERG [human ether-\u00e0-go-go\u2013related gene]) channel are a major safety concern in drug development. In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia. Here, we investigated whether the proarrhythmic risk of existing drugs could be reduced by K\n              <jats:sub>v<\/jats:sub>\n              11.1 allosteric modulators.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Using [\n              <jats:sup>3<\/jats:sup>\n              H]dofetilide-binding assays with membranes of human K\n              <jats:sub>v<\/jats:sub>\n              11.1-expressing human embryonic kidney 293 cells, 2 existing compounds (VU0405601 and ML-T531) and a newly synthesized compound (LUF7244) were found to be negative allosteric modulators of dofetilide binding to the K\n              <jats:sub>v<\/jats:sub>\n              11.1 channel, with LUF7244 showing the strongest effect at 10 \u03bcmol\/L. The K\n              <jats:sub>v<\/jats:sub>\n              11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were significantly decreased by LUF7244. Treatment of confluent neonatal rat ventricular myocyte (NRVM) monolayers with astemizole or sertindole caused heterogeneous prolongation of action potential duration and a high incidence of early afterdepolarizations on 1-Hz electric point stimulation, occasionally leading to unstable, self-terminating tachyarrhythmias. Pretreatment of NRVMs with LUF7244 prevented these proarrhythmic effects. NRVM monolayers treated with LUF7244 alone displayed electrophysiological properties indistinguishable from those of untreated NRVM cultures. Prolonged exposure of NRVMs to LUF7244 or LUF7244 plus astemizole did not affect their viability, excitability, and contractility as assessed by molecular, immunological, and electrophysiological assays.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Allosteric modulation of the K\n              <jats:sub>v<\/jats:sub>\n              11.1 channel efficiently suppresses drug-induced ventricular arrhythmias in vitro by preventing potentially arrhythmogenic changes in action potential characteristics, raising the possibility to resume the clinical use of unintended K\n              <jats:sub>v<\/jats:sub>\n              11.1 blockers via pharmacological combination therapy.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.115.003439","type":"journal-article","created":{"date-parts":[[2016,4,13]],"date-time":"2016-04-13T03:37:39Z","timestamp":1460518659000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Allosteric Modulation of K\n            <sub>v<\/sub>\n            11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias"],"prefix":"10.1161","volume":"9","author":[{"given":"Zhiyi","family":"Yu","sequence":"first","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacobus P.D.","family":"van Veldhoven","sequence":"additional","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriaan P.","family":"IJzerman","sequence":"additional","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin J.","family":"Schalij","sequence":"additional","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dani\u00ebl A.","family":"Pijnappels","sequence":"additional","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura H.","family":"Heitman","sequence":"additional","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine A.F.","family":"de Vries","sequence":"additional","affiliation":[{"name":"From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., 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