title: Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models.
abstract: It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Król
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Ufnal
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; Department of Physiology and Pathophysiology, Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Szulczyk
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Podsadni
authors.affiliation: Department of Experimental Physiology and Pathophysiology, Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Drapała
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turło
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland. Electronic address: maciej.dawidowski@wum.edu.pl.
authors.forename: Maciej
authors.initials: M
authors.lastname: Dawidowski
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004206:Disopyramide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004562:Electrocardiography; D008297:Male; D051379:Mice; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000627:therapeutic use*
chemical_list: C000611225:2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D026941:Sodium Channel Blockers; D004206:Disopyramide
keywords: Antiarrhythmic drug; Anticonvulsant drug; Cardiotoxicity; Disopyramide; Epilepsy; Sodium channels