Stereostructure Activity Relationships of Catecholamines on Human Platelet Function

Chang ho Ahn, Gamal Shams, Robert L. Schotzinger, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The concentration-dependent effects of clonidine, isomers of epinephrine, norepinephrine (NE), isoproterenol, cobefrin and α-methyldopamine, and related desoxy analogs (epinine, dopamine, N-isopropyldopamine) were examined on human platelets. The rank order of aggregatory potency (pD 2 values) was R(-)-epinephrine (6.3) > R(-)-NE (5.9) > (±)-erythro-cobefrin (5.3) > S(+)-epinephrine (4.7) = S(+)-NE (4.7) = clonidine (4.7) = dopamine (4.6) > epinine (4.4) > S(+)-α-methyldopamine (4.3) = R(-)-α-meth-yldopamine (4.3) > (±)-threo-cobefrin (3.7). The isoproterenol isomers and N-isopropyldopamine were inactive as agonists. In 9 of 16 platelet-rich plasma preparations, R(-)-epinephrine, R(-)-NE, and (±)erythro-cobefrin were agonists and the remaining analogs blocked R(-)-NE-induced aggregation with a rank order of inhibitory potencies (pKB values) of clonidine (6.2) > S(+)-α-methyldopamine (5.0) > dopamine (4.6) = R(-)-α-methyldopamine (4.4) ≥ S(+)-NE (4.3) > N-isopropyldopamine (4.1) > S(+)-isoproterenol (3.7) = R(-)-isoproterenol (3.5). Each compound was also able to reverse prostaglandin E 1 (PGE 1 ) (0.1 μM)-induced blockade of the maximal aggregation response to ADP. At high concentrations, R(-)-isoproterenol was more potent than either the S(+)-isomer or desoxy analog, N-isopropyldopamine, in the reversal of PGE 1 inhibition of ADP aggregation. Phentolamine blocked these α 2 -adrenoceptor-mediated actions against PGE 1 on ADP aggregation. The rank order of potency for the reversal of PGE 1 -mediated inhibition of ADP aggregation by these catecholamines was similar to that observed for platelet aggregation. Our results indicate that (i) the stereochemical requirements for the interaction of catecholamines with platelet α 2 -adrenoceptors are in agreement with the Easson-Stedman hypothesis and other α-adrenoceptor tissues; (ii) catecholamines lacking a benzylic hydroxyl group in the R-configuration and/or possessing an N-isopropyl group were α 2 -adrenoceptor antagonists; (iii) clonidine gave quantitatively different responses compared with catecholamines for interaction with α 2 -adrenoceptors; and (iv) inhibition of platelet adenylate cyclase is correlated to the inhibition of epinephrine-induced aggregation response for this series of compounds.

Original languageEnglish (US)
Pages (from-to)149-156
Number of pages8
JournalProceedings of the Society for Experimental Biology and Medicine
Volume194
Issue number2
DOIs
StatePublished - Jan 1 1990
Externally publishedYes

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Deoxyepinephrine
Platelets
Catecholamines
Norepinephrine
Isoproterenol
Blood Platelets
Agglomeration
Adrenergic Receptors
Epinephrine
Clonidine
Prostaglandins E
Adenosine Diphosphate
Dopamine
Isomers
Platelet-Rich Plasma
Phentolamine
Platelet Aggregation
Adenylyl Cyclases
Hydroxyl Radical
Tissue

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Stereostructure Activity Relationships of Catecholamines on Human Platelet Function. / Ahn, Chang ho; Shams, Gamal; Schotzinger, Robert L.; Miller, Duane; Feller, Dennis R.

In: Proceedings of the Society for Experimental Biology and Medicine, Vol. 194, No. 2, 01.01.1990, p. 149-156.

Research output: Contribution to journalArticle

Ahn, Chang ho ; Shams, Gamal ; Schotzinger, Robert L. ; Miller, Duane ; Feller, Dennis R. / Stereostructure Activity Relationships of Catecholamines on Human Platelet Function. In: Proceedings of the Society for Experimental Biology and Medicine. 1990 ; Vol. 194, No. 2. pp. 149-156.
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abstract = "The concentration-dependent effects of clonidine, isomers of epinephrine, norepinephrine (NE), isoproterenol, cobefrin and α-methyldopamine, and related desoxy analogs (epinine, dopamine, N-isopropyldopamine) were examined on human platelets. The rank order of aggregatory potency (pD 2 values) was R(-)-epinephrine (6.3) > R(-)-NE (5.9) > (±)-erythro-cobefrin (5.3) > S(+)-epinephrine (4.7) = S(+)-NE (4.7) = clonidine (4.7) = dopamine (4.6) > epinine (4.4) > S(+)-α-methyldopamine (4.3) = R(-)-α-meth-yldopamine (4.3) > (±)-threo-cobefrin (3.7). The isoproterenol isomers and N-isopropyldopamine were inactive as agonists. In 9 of 16 platelet-rich plasma preparations, R(-)-epinephrine, R(-)-NE, and (±)erythro-cobefrin were agonists and the remaining analogs blocked R(-)-NE-induced aggregation with a rank order of inhibitory potencies (pKB values) of clonidine (6.2) > S(+)-α-methyldopamine (5.0) > dopamine (4.6) = R(-)-α-methyldopamine (4.4) ≥ S(+)-NE (4.3) > N-isopropyldopamine (4.1) > S(+)-isoproterenol (3.7) = R(-)-isoproterenol (3.5). Each compound was also able to reverse prostaglandin E 1 (PGE 1 ) (0.1 μM)-induced blockade of the maximal aggregation response to ADP. At high concentrations, R(-)-isoproterenol was more potent than either the S(+)-isomer or desoxy analog, N-isopropyldopamine, in the reversal of PGE 1 inhibition of ADP aggregation. Phentolamine blocked these α 2 -adrenoceptor-mediated actions against PGE 1 on ADP aggregation. The rank order of potency for the reversal of PGE 1 -mediated inhibition of ADP aggregation by these catecholamines was similar to that observed for platelet aggregation. Our results indicate that (i) the stereochemical requirements for the interaction of catecholamines with platelet α 2 -adrenoceptors are in agreement with the Easson-Stedman hypothesis and other α-adrenoceptor tissues; (ii) catecholamines lacking a benzylic hydroxyl group in the R-configuration and/or possessing an N-isopropyl group were α 2 -adrenoceptor antagonists; (iii) clonidine gave quantitatively different responses compared with catecholamines for interaction with α 2 -adrenoceptors; and (iv) inhibition of platelet adenylate cyclase is correlated to the inhibition of epinephrine-induced aggregation response for this series of compounds.",
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AU - Shams, Gamal

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N2 - The concentration-dependent effects of clonidine, isomers of epinephrine, norepinephrine (NE), isoproterenol, cobefrin and α-methyldopamine, and related desoxy analogs (epinine, dopamine, N-isopropyldopamine) were examined on human platelets. The rank order of aggregatory potency (pD 2 values) was R(-)-epinephrine (6.3) > R(-)-NE (5.9) > (±)-erythro-cobefrin (5.3) > S(+)-epinephrine (4.7) = S(+)-NE (4.7) = clonidine (4.7) = dopamine (4.6) > epinine (4.4) > S(+)-α-methyldopamine (4.3) = R(-)-α-meth-yldopamine (4.3) > (±)-threo-cobefrin (3.7). The isoproterenol isomers and N-isopropyldopamine were inactive as agonists. In 9 of 16 platelet-rich plasma preparations, R(-)-epinephrine, R(-)-NE, and (±)erythro-cobefrin were agonists and the remaining analogs blocked R(-)-NE-induced aggregation with a rank order of inhibitory potencies (pKB values) of clonidine (6.2) > S(+)-α-methyldopamine (5.0) > dopamine (4.6) = R(-)-α-methyldopamine (4.4) ≥ S(+)-NE (4.3) > N-isopropyldopamine (4.1) > S(+)-isoproterenol (3.7) = R(-)-isoproterenol (3.5). Each compound was also able to reverse prostaglandin E 1 (PGE 1 ) (0.1 μM)-induced blockade of the maximal aggregation response to ADP. At high concentrations, R(-)-isoproterenol was more potent than either the S(+)-isomer or desoxy analog, N-isopropyldopamine, in the reversal of PGE 1 inhibition of ADP aggregation. Phentolamine blocked these α 2 -adrenoceptor-mediated actions against PGE 1 on ADP aggregation. The rank order of potency for the reversal of PGE 1 -mediated inhibition of ADP aggregation by these catecholamines was similar to that observed for platelet aggregation. Our results indicate that (i) the stereochemical requirements for the interaction of catecholamines with platelet α 2 -adrenoceptors are in agreement with the Easson-Stedman hypothesis and other α-adrenoceptor tissues; (ii) catecholamines lacking a benzylic hydroxyl group in the R-configuration and/or possessing an N-isopropyl group were α 2 -adrenoceptor antagonists; (iii) clonidine gave quantitatively different responses compared with catecholamines for interaction with α 2 -adrenoceptors; and (iv) inhibition of platelet adenylate cyclase is correlated to the inhibition of epinephrine-induced aggregation response for this series of compounds.

AB - The concentration-dependent effects of clonidine, isomers of epinephrine, norepinephrine (NE), isoproterenol, cobefrin and α-methyldopamine, and related desoxy analogs (epinine, dopamine, N-isopropyldopamine) were examined on human platelets. The rank order of aggregatory potency (pD 2 values) was R(-)-epinephrine (6.3) > R(-)-NE (5.9) > (±)-erythro-cobefrin (5.3) > S(+)-epinephrine (4.7) = S(+)-NE (4.7) = clonidine (4.7) = dopamine (4.6) > epinine (4.4) > S(+)-α-methyldopamine (4.3) = R(-)-α-meth-yldopamine (4.3) > (±)-threo-cobefrin (3.7). The isoproterenol isomers and N-isopropyldopamine were inactive as agonists. In 9 of 16 platelet-rich plasma preparations, R(-)-epinephrine, R(-)-NE, and (±)erythro-cobefrin were agonists and the remaining analogs blocked R(-)-NE-induced aggregation with a rank order of inhibitory potencies (pKB values) of clonidine (6.2) > S(+)-α-methyldopamine (5.0) > dopamine (4.6) = R(-)-α-methyldopamine (4.4) ≥ S(+)-NE (4.3) > N-isopropyldopamine (4.1) > S(+)-isoproterenol (3.7) = R(-)-isoproterenol (3.5). Each compound was also able to reverse prostaglandin E 1 (PGE 1 ) (0.1 μM)-induced blockade of the maximal aggregation response to ADP. At high concentrations, R(-)-isoproterenol was more potent than either the S(+)-isomer or desoxy analog, N-isopropyldopamine, in the reversal of PGE 1 inhibition of ADP aggregation. Phentolamine blocked these α 2 -adrenoceptor-mediated actions against PGE 1 on ADP aggregation. The rank order of potency for the reversal of PGE 1 -mediated inhibition of ADP aggregation by these catecholamines was similar to that observed for platelet aggregation. Our results indicate that (i) the stereochemical requirements for the interaction of catecholamines with platelet α 2 -adrenoceptors are in agreement with the Easson-Stedman hypothesis and other α-adrenoceptor tissues; (ii) catecholamines lacking a benzylic hydroxyl group in the R-configuration and/or possessing an N-isopropyl group were α 2 -adrenoceptor antagonists; (iii) clonidine gave quantitatively different responses compared with catecholamines for interaction with α 2 -adrenoceptors; and (iv) inhibition of platelet adenylate cyclase is correlated to the inhibition of epinephrine-induced aggregation response for this series of compounds.

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