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

R. R. Ruffolo, J. W. Banning, P. N. Patil, A. Hamada, D. D. Miller

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Abstract

The alpha and beta adrenoceptor-mediated effects of the enantiomers of a novel optically active catecholamidine (3,4,α-trihydroxyphenyl-acetamidine) and corresponding desoxy derivative (3,4-dihydroxyphenyl-acetamidine) have been 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 carbon 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 two enantiomers and desoxy derivative of the catecholamidine was desoxy > (-) > (+) or deoxy ≥ (-) > (+) 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 by us 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 were also found to possess 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. These results suggest that important qualitative differences exist between the stereochemical demands made by alpha and beta adrenoceptors and that these differences may be uncovered by optically active amidines and imidazolines, but not by optically active phenethylamines. It is also concluded that optically active catecholamidines interact in a similar manner with alpha adrenoceptors as optically active catecholimidazolines, but that these two classes of alpha adrenoceptor agonists do not interact with alpha adrenoceptors in a similar manner as the phenethylamines.

Original languageEnglish (US)
Pages (from-to)469-476
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume226
Issue number2
StatePublished - Oct 13 1983

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Adrenergic Agents
Adrenergic Receptors
Phenethylamines
In Vitro Techniques
Amidines
Imidazolines
Hydroxyl Radical
Carbon

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

@article{b1e64722897b4ba8988dc212f0488a4d,
title = "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",
abstract = "The alpha and beta adrenoceptor-mediated effects of the enantiomers of a novel optically active catecholamidine (3,4,α-trihydroxyphenyl-acetamidine) and corresponding desoxy derivative (3,4-dihydroxyphenyl-acetamidine) have been 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 carbon 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 two enantiomers and desoxy derivative of the catecholamidine was desoxy > (-) > (+) or deoxy ≥ (-) > (+) 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 by us 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 were also found to possess 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. These results suggest that important qualitative differences exist between the stereochemical demands made by alpha and beta adrenoceptors and that these differences may be uncovered by optically active amidines and imidazolines, but not by optically active phenethylamines. It is also concluded that optically active catecholamidines interact in a similar manner with alpha adrenoceptors as optically active catecholimidazolines, but that these two classes of alpha adrenoceptor agonists do not interact with alpha adrenoceptors in a similar manner as the phenethylamines.",
author = "Ruffolo, {R. R.} and Banning, {J. W.} and Patil, {P. N.} and A. Hamada and Miller, {D. D.}",
year = "1983",
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journal = "Journal of Pharmacology and Experimental Therapeutics",
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T1 - Evaluation of the adrenergic effects of a novel optically active catecholamidine in vitro and in vivo

T2 - Differential application of the Easson-Stedman hypothesis to alpha and beta adrenoceptors

AU - Ruffolo, R. R.

AU - Banning, J. W.

AU - Patil, P. N.

AU - Hamada, A.

AU - Miller, D. D.

PY - 1983/10/13

Y1 - 1983/10/13

N2 - The alpha and beta adrenoceptor-mediated effects of the enantiomers of a novel optically active catecholamidine (3,4,α-trihydroxyphenyl-acetamidine) and corresponding desoxy derivative (3,4-dihydroxyphenyl-acetamidine) have been 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 carbon 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 two enantiomers and desoxy derivative of the catecholamidine was desoxy > (-) > (+) or deoxy ≥ (-) > (+) 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 by us 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 were also found to possess 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. These results suggest that important qualitative differences exist between the stereochemical demands made by alpha and beta adrenoceptors and that these differences may be uncovered by optically active amidines and imidazolines, but not by optically active phenethylamines. It is also concluded that optically active catecholamidines interact in a similar manner with alpha adrenoceptors as optically active catecholimidazolines, but that these two classes of alpha adrenoceptor agonists do not interact with alpha adrenoceptors in a similar manner as the phenethylamines.

AB - The alpha and beta adrenoceptor-mediated effects of the enantiomers of a novel optically active catecholamidine (3,4,α-trihydroxyphenyl-acetamidine) and corresponding desoxy derivative (3,4-dihydroxyphenyl-acetamidine) have been 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 carbon 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 two enantiomers and desoxy derivative of the catecholamidine was desoxy > (-) > (+) or deoxy ≥ (-) > (+) 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 by us 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 were also found to possess 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. These results suggest that important qualitative differences exist between the stereochemical demands made by alpha and beta adrenoceptors and that these differences may be uncovered by optically active amidines and imidazolines, but not by optically active phenethylamines. It is also concluded that optically active catecholamidines interact in a similar manner with alpha adrenoceptors as optically active catecholimidazolines, but that these two classes of alpha adrenoceptor agonists do not interact with alpha adrenoceptors in a similar manner as the phenethylamines.

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