β1- and β2-Adrenoceptor antagonist activity of a series of para-substituted N-isopropylphenoxypropanolamines

Abstract To further explore the structure-activity relationships of β-adrenoceptor (β-AR) antagonists, a series of 25 para -substituted N -isopropylphenoxy-propanolamines were synthesised, nine of which are new compounds. All have been examined for their ability to antagonise β 1 -ARs in rat atria and β 2 -ARs in rat trachea. Substitution in the para -position of the phenyl ring is thought to confer β 3 -specificity and the selectivity of these compounds for the β 1 -AR ranges from 1.5–234. None of the compounds tested were selective for the β 2 -AR. Of the 25 compounds studied, 22 had reasonable (pA 2 > 7) potencies for the rat β 1 -AR. Only compound 1 displayed reasonable (pA 2 > 7) potency for the rat β 2 -AR. Twenty two compounds were used as the training set for comparative molecular field analysis (CoMFA) of antagonist potency (pA 2 ) at the rat β 1 - and β 2 -ARs. The inclusion of a number of additional physical characteristics improved the QSAR analysis over models derived solely using the CoMFA electrostatic and steric fields. The final models predicted the β 1 - and β 2 -AR potency of the compounds in the training set with high accuracy (r 2 = 0.93 and 0.86 respectively). The final β 1 -AR model predicted the β 1 -potencies of two out of the three test compounds, not included in the training set, with residual pA 2 values 2 -AR model (residual pA 2 values