Prediction of the non-specific cardiodepressant effects of beta-adrenoceptor blocking agents in vitro and in vivo by means of the Hansch analysis

Hydrophobicity (n-octanol/buffer partition coefficients) of six 1-alkylamino-3-(2-nitrilophenoxy)-propan-2-ol derivatives with different substituents at the amino group (Kö 1439, Kö 1561, Kö 1560, Kö 1313, Kö 1366, Kö 1500), and of five 1-isopropylamino-3-(alkylphenoxy)-propan-2-ol derivatives with different ring substituents (Kö 592, Kö 707, Kö 1030, Kö 1124, Kö 1292), with β-adrenoceptor blocking properties, was correlated with the non-specific cardiodepressant effects of the drugs. Influence on the conduction velocity of the frog heart was studied in vitro and influence of the drugs on dp/dt_max in anaesthetized cats after β-adrenoceptor blockade was measured in vivo. The physicochemical and pharmacological data were analysed by the method of Hansch.The partition coefficients of the β-adrenoceptor blocking drugs ranged more than three orders of magnitude. The differences in hydrophobicity were solely dependent on the sum of the hydrophobic substituents of the drug molecules at the phenyl ring and at the amino group. Slowing of conduction velocity in vitro was more pronounced the higher the partition coefficients of the two series of the Kö compounds investigated; multiple regression analysis revealed parabolic correlation equations between hydrophobicity and pharmacological effects, depending on the experimental conditions (incubation time, mode of stimulation of the preparation) used. A parabolic correlation was also observed between hydrophobicity and decrease of dp/dt_max in vivo. Similar correlation equations were obtained when the hydrophobic properties of the compounds were calculated according to the method of Hansch.From the physicochemical, pharmacological, and analytical data it is concluded that the non-specific cardiodepressant effects of β-adrenoceptor blocking drugs can be predicted for given pharmacological systems by determination or by calculation of the hydrophobicity of the drug molecules, irrespectively of the site of the hydrophobic substituents (whether at the ring system or at the amino group).