Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
Bioorg Med Chem. 2012 Apr 1;20(7):2290-303. doi: 10.1016/j.bmc.2012.02.009. Epub 2012 Feb 13.
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.
研究了一系列海因（2a-21a）苯哌嗪衍生物的α(1)-肾上腺素受体亲和力、hERG K(+)拮抗特性和抗心律失常活性之间的关系。合成了新的化合物，并使用[（3）H]-普拉唑辛作为选择性放射性配体，在放射性配体结合测定中测试它们对α(1)-肾上腺素受体的亲和力。在正常血压大鼠体内，在肾上腺素和氯化钡诱导的心律失常模型中测试了苯哌嗪衍生物的抗心律失常活性，以及它们对心电图成分和血压的影响。使用 QikProp 程序对最有效的抗心律失常剂的 hERG K(+)拮抗特性进行了计算机模拟研究。在肾上腺素诱导的心律失常中，具有最高的α(1)-肾上腺素受体亲和力（K(i)=4.7 nM）和最强的抗心律失常活性的是 1-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁基)-3-甲基-5,5-二苯基咪唑烷-2,4-二酮盐酸盐（19a）。结果表明，在肾上腺素模型中，α(1)-AR 亲和力（pK(i)）与抗心律失常活性（ED(50)）之间存在显著相关性（R(2)=0.92，p <0.005）。通过计算机模拟方法预测，所研究的苯哌嗪海因衍生物对 hERG K(+)通道的影响表明它们具有 hERG K(+)阻断特性。
