Synthesis and .alpha.2-adrenoceptor effects of substituted catecholimidazoline and catecholimidazole analogs in human platelets

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Abstract
It is known that the steric requirements for the interactions of catecholamines and catecholimidazolines with .alpha.1- and .alpha.2-adrenoceptors are different. New analogues of desoxycatecholimidazoline (1), desoxycatecholimidazole (3), benzylic hydroxyl substituted imidazole (4), and the aromatic fluorine substitution analogues of 1 at the 2 (5), 5 (6), and 6 (7) positions, and a set of asymmetric 4-substituted catecholimidazolines, S-8 and R-8, were prepared and tested for interaction with .alpha.2-adrenoceptors in human platelets. With the exception of 3, all compounds were selective for .alpha.-adrenoceptor-mediated responses in human platelets. Introduction of a double bond in imidazoline 1 to give an imidazole 3 or the introduction of a benzylic hydroxy group to 3, as in 4, reduced the inhibition of platelet aggregation with a rank order potency of 1 > 3 > 4. Fluorine atom substitution at the 2-, 5-, or 6-positions only slightly modified the inhibitory activity of 1. Each analogue (1, 3-7) produced .alpha.2-mediated inhibition of platelet adenylate cyclase and can be classified as a partial agonist. The inhibition potency of S-8 and R-8 against epinephrine-induced aggregatory responses were greatly different, and only R-8 and 4 were .alpha.2-agonists on human platelet function. Our studies provide further evidence for the differential interaction of catecholamines and catecholimidazolines in .alpha.1- and .alpha.2-adrenoceptor systems.