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Title: beta(1)- and beta(2)-Adrenoceptor antagonist activity of a series of para-substituted N-isopropylphenoxypropanolamines.
Austin Authors: Louis, SN;Nero, Tracy L;Iakovidis, D;Colagrande, FM;Jackman, GP;Louis, WJ
Affiliation: Clinical Pharmacology and Therapeutics Unit, The University of Melbourne, Department of Medicine, Austin and Repatriation Medical Centre 3084, Victoria, Heidelberg, Australia
Issue Date: 1-Nov-1999
Publication information: European Journal of Medicinal Chemistry; 34(11): 919-937
Abstract: To further explore the structure-activity relationships of beta-adrenoceptor (beta-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 beta(1)-ARs in rat atria and beta(2)-ARs in rat trachea. Substitution in the para-position of the phenyl ring is thought to confer beta(3)-specificity and the selectivity of these compounds for the beta(1)-AR ranges from 1.5-234. None of the compounds tested were selective for the beta(2)-AR. Of the 25 compounds studied, 22 had reasonable (pA(2) > 7) potencies for the rat beta(1)-AR. Only compound 1 displayed reasonable (pA(2) > 7) potency for the rat beta(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 beta(1)- and beta(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 beta(1)- and beta(2)-AR potency of the compounds in the training set with high accuracy (r(2) = 0.93 and 0.86 respectively). The final beta(1)-AR model predicted the beta(1)-potencies of two out of the three test compounds, not included in the training set, with residual pA(2) values < -0.14, whereas the test compounds were not as well predicted by our final beta(2)-AR model (residual pA(2) values < -0.38).
Gov't Doc #: 10889317
Type: Journal Article
Appears in Collections:Journal articles

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