Comparisons of Biochemical and Pharmacological Properties of Prostacyclins with Modified ω-Side Chain
PGI2-analogs in which the n-pentyl moiety in position 15 was replaced by several residues, were subjected to structure-activity studies. Some of the modified PGI2’s showed remarkable potency in regard to antiplatelet and vasodilator actions. in order to evaluate these potencies the inhibition of arachidonic acid induced platelet aggregation in human platelet rich plasma, relaxation of bovine coronary artery (BCA) and systemic blood pressure (BP) in the anesthetized rat were determined. Platelet aggregation was inhibited by PGI2 with an IC50 approx. 3-10-9M, BP was decreased in a dose dependent manner with an ED25, of 0.23 ug/kg i.v. and a marked relaxation of BCA was observed. Similar results were obtained with PGI2-methylester. Substitution of the n-pentyl moiety by cyclohexyl, 3-furyl-2-ethyl or 3-thienyl-oxymethyl resulted in PGI2- and PGI2-methyl-ester-analogs with high biological activity, whereas substitution by T6,16-dimethyl-18-oxa-alkyl or phenoxymethyl caused a loss of activity in the models used. The potency of the prostacyclins in the platelet model seem to depend upon their ability to elevate the platelet cyclo-AMP level. Thus the antiplatelet potency of modified PGI2’s may reflect their ability to affect the adenylate cyclase system.