Aggregation of platelets induced by novel synthetic secoprostaglandins.

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Abstract
Two series of 8-acetyl-12-hydroxyalkadienoic acids and 14-hydroxy-9-oxoalkadienoic acids which can be regarded as 11,12- and 8,12-secoprostaglandin E2 were synthesized and evaluated for their biological properties. Key members of each series, 11,12-(8Ac-HAD) and 8,12-seco-11-norprostaglandin E2 (14H-OAD), induced platelet aggregation in rabbits which was inhibited by preincubation of platelet rich plasma with prostaglandin I2 but not inhibited by indomethacin. 8Ac-HAD produced dose-dependent potent contraction of rabbit aorta. Injection of 8Ac-HAD (1 mg/kg) into rat veins induced sudden death of the animal. Both compounds were stable and platelet aggregating activity did not decrease at least for 4 h at 0.degree. C. Structure-activity relationship studies of the series were carried out. Reduction of the acetyl carbonyl and methoxime formation of 8Ac-HAD lowered platelet aggregating activity, and 8-propionyl substituent and 12-deoxy derivative of 8Ac-HAD showed no activity. 12(R)-Isomer and dl-12-methyl derivative of 8Ac-HAD retained the platelet aggregating activity. Modification of .omega.-chain did not cause any essential effect on the activity. Unlike 8Ac-HAD, several modifications of 14H-OAD failed to maintain the aggregating activity.