SOME BIOCHEMICAL-STUDIES WITH SQ 26271 - A STABLE PARTIAL PROSTACYCLIN AGONIST IN THE HUMAN-PLATELET

A newly synthesized 9α-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26271 (8(S)9(S)11(R)12(S)-9,11-epoxy-9α- homo-5(Z),13(E)-15(R)-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation at concentrations which did not affect thromboxane B2 (TXB2) levels with an I50 value of 0.25 μM. It also was a potent inhibitor of platelet aggregation caused by collagen, 9,11- AzoPGH2, SQ 24810 (9,11-epoxy-9α-homo-5(Z),13(E)-15α- hydroxyprostadienoic acid) and epinephrine (secondary phase). However, it had little or no effect on thromboxane or prostaglandin synthetase activities. Moreover, SQ 26271 also inhibited the primary phase of epinephrine- and ADP- induced aggregation. In addition SQ 26271 caused a 3-fold increase in platelet adenylate cyclase activity, partially blocked prostacyclin stimulated adenylate cyclase activity and caused a 6-fold elevation of cyclic AMP levels in intact platelets, which was blocked by SQ 22536 (9-tetrahy- dro-2-furyl)adenine), an inhibitor of platelet adenylate cyclase activity. Finally, the inhibition of platelet aggregation by SQ 26271 was potentiated by an inhibitor of cyclic AMP phosphodiesterase (SQ 20009, etazolate), and reversed by SQ 22536. The above data indicate that SQ 26271 is a stable partial agonist of the prostacyclin receptor in human blood platelets.