Gortner L, Hellenbrecht D
University Children's Hospital, Ulm/Donau, Fed. Rep. of Germany.
Arzneimittelforschung. 1988 Dec;38(12):1796-9.
The correlations between the physicochemical properties (n-octanol-buffer partition coefficients, P) of two series of N-alkylated and ring alkylated beta-adrenoceptor blocking phenoxypropanolamines and their antiarrhythmic activities were studied. For this purpose dose-response curves of the influence on the ventricular arrhythmia threshold (VAT) and on heart rate (HR) were determined in the anaesthetized guinea pig. The degree of N-alkylation correlated with the potency of the drugs to raise VAT and to lower HR. Intraventricular conduction was likewise depressed. Increasing ring alkylation did not consistently further increase biological activity. The combined data from series of drugs showed statistically significant parabolic correlations between hydrophobicity (log P' for pH 7.4) and the biological responses. It is concluded that the nonspecific antiarrhythmic and negative chronotropic activity of the investigated beta-adrenoceptor blocking drugs largely depend on their lipophilic properties. In addition steric and pharmacokinetic factors may be operative.
研究了两类N-烷基化和环烷基化的β-肾上腺素受体阻断苯氧丙醇胺的物理化学性质（正辛醇-缓冲液分配系数，P）与其抗心律失常活性之间的相关性。为此，在麻醉的豚鼠中测定了对室性心律失常阈值（VAT）和心率（HR）影响的剂量-反应曲线。N-烷基化程度与药物提高VAT和降低HR的效力相关。室内传导同样受到抑制。环烷基化程度的增加并没有持续进一步提高生物活性。一系列药物的综合数据显示，疏水性（pH 7.4时的log P'）与生物反应之间存在统计学上显著的抛物线相关性。得出的结论是，所研究的β-肾上腺素受体阻断药物的非特异性抗心律失常和负性变时活性在很大程度上取决于它们的亲脂性。此外，空间位阻和药代动力学因素可能也起作用。
