Alteration of relative affinities toward myocardial and vascular β adrenoceptors induced by side-chain substitution of aryloxypropanolamines1

Article abstract of DOI:10.1021/jm00205a016

Several conformationally defined aryloxypropanolamines of the type ArOCH₂CH(OH)CH(R)NHR₁ have been synthesized and tested in vivo for β-adrenoceptor blockade. Key intermediates in the syntheses were the appropriate cis- and trans-disubstituted olefins. Epoxidation of the olefins, followed by amination of the resulting cis- and trans-epoxides, yielded the desired diastereomeric model compounds with a defined threo and erythro stereochemistry, respectively. All active compounds in this series exhibit a simple, bimolecular, competitive antagonism at β adrenoceptors. Proper substitutions of the alkanolamine side chain result in vascular selective or cardioselective β-adrenoceptor antagonists, probably as a consequence of the sterically altered ability to interact with β₁ and β₂ adrenoceptors. dl-erythro-1-Phenoxy-3-[3,4-dimethoxyphenethyl)amino] butan-2-ol is a cardioselective β-adrenoceptor antagonist with a selectivity ratio significantly higher than that of practolol (β₁/β₂>40 vs. β₁/β₂=22) but of equal potency (pA₂ values = 6.66 and 6.64, respectively). Phenyl substitution at C-3 of the alkanolamine side chain drastically reduces affinity to both types of β adrenoceptors (pA₂<5.0), thus representing a cutoff point. It is concluded that steric factors, as manifested by bulk tolerance at various parts of the aryloxypropanolamine side chain, are major determinants of affinity toward β-adrenoceptor subtypes. β-Adrenoceptor blockade is unrelated to the lipophilic character of the test compounds.