Effects of alpha 2-adrenoceptor agonists and of related compounds on aggregation of, and on adenylate cyclase activity in, human platelets.

ABSTRACT

A range of 2-(,5-dihydroimidazolyl)-benzene, -quinoline, and -quinoxaline derivatives and 2-morpholino-4-catechol have been characterized as agonists or partial agonists for human platelet aggregation; and for inhibition of adenylate cyclase by measurement of their effect on platelet [cyclic-3',5'-AMP]. Antagonist activity for these compounds versus adrenaline as agonist has also been assessed for these two responses. The compounds can be divided into 4 groups. Group I contains compounds that are agonists for both responses; group II, compounds that are agonists for inhibition of adenylate cyclase but antagonists for the aggregatory response; group III, compounds that are agonists for the aggregatory response but are antagonists for inhibition of adenylate cyclase by adrenaline; and group IV, compounds that are antagonists for both responses. In group I the EC50 values for induction of aggregation are not significantly different from the EC50 values for inhibition of adenylate cyclase except for 2-morpholino-4-catechol which is significantly more potent as an inhibitor of adenylate cyclase. In group IV a linear correlation is observed between the K1 values for the two responses for 8 compounds but 2 other compounds do not conform to this correlation. The data are not consistent with a model in which a single chi 2-adrenoceptor mediates both the aggregatory response and inhibition of adenylate cyclase and hence support a model in which unique chi 2-adrenoceptors mediate these two responses.