Analysis of the biological activity of azoprostanoids in human platelets

A structure-activity analysis of seven different azoprostanoids in human platelets and rat aortas has shown that discrete changes in the prostanoid skeleton induce marked changes in biological activity. The 15S-hydroxyl group is important for agonist activity in the platelet (pro-aggregatory) and in the aorta (vasoconstriction). Removal of the 15S-hydroxyl results in a compound that inhibits the thromboxane synthetase and platelet aggregation, and is a much weaker constrictor of the aorta. The 13,14 double bond is more important for agonist activity on the aorta than the 5,6 double bond of the prostanoid skeleton. Completely saturated molecules that are 15-deoxy still retain considerable activity on the aorta, but are two orders of magnitude less active as inhibitors of the thromboxane synthetase and aggregation than the azoprostanoid with both 5,6 and 13,14 double bonds. Compounds that exhibit no agonist activity in platelets still retain considerable agonist activity on the aorta, suggesting that the thromboxane A2 receptor in platelets may be different from the thromboxane A2 receptor in blood vessels.