Stereostructure Activity Relationships of Catecholamines on Human Platelet Function

Abstract

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 (pD₂ 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 (pK_B 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 E₁ (PGE₁) (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 PGE₁ inhibition of ADP aggregation. Phentolamine blocked these α ₂-adrenoceptor-mediated actions against PGE₁ on ADP aggregation. The rank order of potency for the reversal of PGE₁-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.