Referenced in: none

Automatically associated channels: Kv11.1

Title: Antiarrhythmic properties of phenylpiperazine derivatives of phenytoin with α₁-adrenoceptor affinities.

Authors: Jadwiga Handzlik, Marek Bajda, Małgorzata Zygmunt, Dorota Maciag, Małgorzata Dybała, Marek Bednarski, Barbara Filipek, Barbara Malawska, Katarzyna Kieć-Kononowicz

Journal, date & volume: Bioorg. Med. Chem., 2012 Apr 1 , 20, 2290-303

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22381672

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.