title: Antiarrhythmic properties of phenylpiperazine derivatives of phenytoin with α₁-adrenoceptor affinities.
abstract: An association between α(1)-adrenoceptor affinities, hERG K(+)-antagonistic properties and antiarrhythmic activities for a series of phenylpiperazine derivatives of hydantoin (2a-21a) was investigated. New compounds were synthesized and tested for their affinity for α(1)-adrenoceptors in radioligand binding assay using [(3)H]-prazosin as a selective radioligand. Antiarrhythmic activities in adrenaline- and barium chloride-induced arrhythmia models, an influence of the phenylpiperazine derivatives on the ECG-components and blood pressure were tested in vivo in normotensive rats. The hERG K(+)-antagonistic properties of the most potent antiarrhythmic agents were investigated in silico by the use of program QikProp. The highest α(1)-adrenoceptor affinity (K(i)=4.7 nM) and the strongest antiarrhythmic activity in adrenaline induced arrhythmia (ED(50)=0.1 mg/kg) was found for 1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione hydrochloride (19a). The results indicated a significant correlation between α(1)-AR affinities (pK(i)) and antiarrhythmic activity (ED(50)) in adrenaline model (R(2)=0.92, p <0.005). Influence of the examined phenylpiperazine hydantoin derivatives on hERG K(+) channel, predicted by means of in silico methods, suggested their hERG K(+)-blocking properties.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.forename: Dorota
authors.initials: D
authors.lastname: Maciąg
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dybała
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C573386:1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione hydrochloride; D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D048289:Imidazolidines; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D010672:Phenytoin; C031503:phenylpiperazine