.beta.-Adrenoceptor studies. 2. Effects of alkyl substitution on .beta.-adrenoceptor blocking, antiarrhythmic, and local anesthetic activities of 1,1'-(o-phenylenedioxy)bis(3-isopropylamino-2-propanol)

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Abstract
A series of bis(2-hydroxy-3-isopropylaminopropyl) ethers of nuclear-substituted catechols was synthesized and examined in vitro for .beta.-adrenoceptor blocking activity, antagonism of ouabain-induced arrhythmias [guinea pig] and local anesthetic activity [frog]. Both tracheal and right atrial .beta.-adrenoceptor blocking activity were markedly decreased by alkyl substitution in position 3 of the parent catechol diether (1). Substitution in position 4 still lowered the affinity to cardiac .beta.-adrenoceptors whereas the potency on tracheal receptors was only marginally changed. Antagonism to ouabain-induced arrhythmias and local anesthetic activity increased with introduction of alkyl substituents in the 3 and 4 position. The partition coefficient 1-octanol-phosphate buffer, pH 7.40, of 1 did not change significantly by 3- and 4-methyl substitution. Stepwise multiple regression analyses were performed using log P or .pi. values in combination with pKa(m), Es, or .sigma.. With cardiac .beta.-adrenoceptor blocking activity the optimal equation contained Es and .pi. parameters, tracheal activity appeared to depend mainly on the Es parameter, whereas for antiarrhythmic and local anesthetic activities the lipophilicity of the substituents appeared to be the determinant factor.

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