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Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics

1 Two prostaglandin endoperoxide analogues, EP 035 and EP 157, behave as specific thromboxane receptor antagonists on isolated smooth muscle preparations such as rabbit aorta, dog saphenous vein and guinea‐pig trachea. However, in human platelet‐rich plasma (PRP) they produce an unsurmountable block of aggregation induced by a wide range of agents (ADP, platelet‐activating factor, thrombin); this inhibitory profile is typical of that seen with either prostaglandin I2 (PGI2) or PGD2. 2 EP 035 and EP 157 induce large increases in cyclic AMP levels (up to 20 times basal) in human PRP. Simultaneous exposure to PGE, markedly reduces their effect on cyclic AMP; exposure to PGD2 is much less effective in this respect. The adenylate cyclase inhibitor SQ 22,536 opposes the inhibitory action of EP 035, EP 157, iloprost (a stable PGI2 analogue) and PGD2 on platelet aggregation. However, the xanthone derivative AH 6809 blocks the inhibitory action of PGD2 but does not affect EP 035, EP 157 and PGI2 and its structural analogues. 3 EP 035 and EP 157 displace [3H]‐iloprost binding to the PGI2 receptor on human platelet membranes. Displacing ability is ranked as follows: iloprost > 6a‐carba PGI2 > EP 157 > EP 035 > EP 164 (α‐dinor derivative of EP 157). This order of potency is the same as that found for activation of adenylate cyclase in homogenates of washed human platelets and for inhibition of aggregation in washed human platelets. 4 The activities of EP 035 and EP 157 were studied in two other systems containing PGI2 receptoradenylate cyclase complexes, the NCB‐20 cell line and human lung tissue. In both cases stimulation of adenylate cyclase was found but maximum rates were below that achieved with iloprost. These effects of EP 035 and EP 157 could be correlated with their abilities to displace [3H]‐iloprost binding. 5 These results indicate that EP 035 and EP 157 inhibit the aggregation of human platelets by acting as agonists at the PGI2 receptor linked to adenylate cyclase. They represent a class of compound with both thromboxane receptor blocking activity and prostacyclin mimetic activity.