Evaluation of the adrenergic effects of a novel optically active catecholamidine in vitro and in vivo: differential application of the Easson-Stedman hypothesis to alpha and beta adrenoceptors
Ruffolo, R.R.; Banning, J.W.; Patil, P.N.; Hamada, A.; Miller, D.D.
Journal of Pharmacology and Experimental Therapeutics 226(2): 469-476
1983
ISSN/ISBN: 0022-3565 PMID: 6308208 Document Number: 208212
The .alpha.- and .beta.-adrenoceptor-mediated effects of the enantiomers of a novel optically active catecholamidine (3,4,.alpha.-trihydroxyphenyl-acetamidine) and corresponding desoxy derivative (3,4-dihydroxyphenyl-acetamidine) were investigated in vitro and in vivo to assess the applicability of the Easson-Stedman Hypothesis to the adrenergic activities of this class of agonist. The Easson-Stedman Hypothesis proposes that the enantiomers of optically active adrenoceptor agonists possessing an asymmetric hydroxyl-substituted benzylic C atom, and the corresponding desoxy derivative, will have the following relative potencies: (-)-enantiomer > (+)-enantiomer = desoxy derivative. The enantiomers of the optically active catecholamidine and the corresponding desoxy derivative were potent agonists at .alpha.1- and .alpha.2 adrenoceptors, but displayed a distinct selectivity for .alpha.1-adrenoceptors. The rank order of potency at both .alpha.-adrenoceptor subtypes for the 2 enantiomers and desoxy derivative of the catecholamidine was desoxy > (-) > (+) or desoxy .gtoreq. (-) > (+) which indicates that the .alpha.-adrenoceptor-mediated effects of these catecholamidines do not conform to that order of potency predicted by the Easson-Stedman Hypothesis. The rank order of potency for the enantiomers and corresponding desoxy derivative of the catecholamidine at .alpha.-adrenoceptors is identical to the order of potency obtained previously for the enantiomers and desoxy derivative of an optically active catecholimidazoline, but is different from the rank order of potency obtained with optically active phenethylamines which adhere strictly to the Easson-Stedman Hypothesis. The enantiomers and desoxy derivative of the optically active catecholamidine possessed weak activity at both .beta.1- and .beta.2-adrenoceptors, but, in contrast to their .alpha.-adrenoceptor-mediated effects, the activities of these compounds at both .beta.-adrenoceptor subtypes did conform to the rank order of potency predicted by the Easson-Stedman Hypothesis. Important qualitative differences apparently exist between the stereochemical demands made by .alpha.- and .beta.-adrenoceptors and these differences may be uncovered by optically active amidines and imidazolines, but not by optically active phenethylamines. Optically active catecholamidines evidently interact in a similar manner with .alpha.-adrenoceptors as optically a ctive catecholimidazolines, but these 2 classes of .alpha.-adrenoceptor agonists do not interact with .alpha.-adrenoceptors in a similar manner as the phenethylamines.