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Abstract
The antiarrhythmic and cardiac electrophysiological effects of SZV-2649 that contains a 2,6-diiodophenoxy moiety but lacks the benzofuran ring system present in amiodarone, were studied in mammalian cell line, rat and dog cardiac preparations. SZV-2649 exerted antiarrhythmic effects against coronary artery occlusion/reperfusion induced ventricular arrhythmias in rats and in acetylcholine- and burst stimulation induced atrial fibrillation in dogs. SZV-2649 inhibited hERG and GIRK currents in HEK cells (IC50: 342 and 529 nM, respectively). In canine ventricular myocytes, SZV-2649 (10 µM) decreased the densities of IKr, and Ito outward and INaL and ICaL inward currents. The compound (2.5–10 µM) elicited Class IB type Vmax reducing and Class III type action potential duration prolonging effects in dog right ventricular muscle preparations. In canine atrial muscle, SZV-2629 (2.5–10 µM) moderately prolonged action potential duration and this effect was greatly augmented in preparations pretreated with 1 µM carbachol. In conclusion, SZV-2649, has antiarrhythmic effects based on its multiple ion channel blocking properties. Since its chemical structure substantially differs from that of amiodarone, it is expected that SZV-2649 would exhibit fewer adverse effects than the currently used most effective multichannel inhibitor drug amiodarone and may be a promising molecule for further development.
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1 University of Szeged, Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625)
2 University of Szeged, Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625); Hungarian Research Network, HUN-REN-SZTE Stereochemistry Research Group, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0004 9284 0620)
3 University of Szeged, Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625)
4 Semmelweis University, Department of Organic Chemistry, Budapest, Hungary (GRID:grid.11804.3c) (ISNI:0000 0001 0942 9821); University of Veterinary Medicine, National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, Budapest, Hungary (GRID:grid.483037.b) (ISNI:0000 0001 2226 5083)
5 Semmelweis University, Department of Organic Chemistry, Budapest, Hungary (GRID:grid.11804.3c) (ISNI:0000 0001 0942 9821)
6 University of Szeged, Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625); Hungarian Research Network, HUN-REN-SZTE Research Group for Cardiovascular Pharmacology, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0004 9284 0620)
7 University of Szeged, Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625); Hungarian Research Network, HUN-REN-SZTE Research Group for Cardiovascular Pharmacology, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0004 9284 0620); University of Szeged, Interdisciplinary Research and Development and Innovation Centre of Excellence, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625)
8 University of Szeged, Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625); University of Szeged, Interdisciplinary Research and Development and Innovation Centre of Excellence, Szeged, Hungary (GRID:grid.9008.1) (ISNI:0000 0001 1016 9625)