PHARMACOLOGICAL PROPERTIES OF THE NEW STABLE PROSTACYCLIN ANALOG 3-OXA-METHANO-PROSTAGLANDIN I(1)

The pharmacological characteristics of the 3-oxa-methano-prostaglandin I-1 compound (+)-methyl [2-[(2R, 3aS, 4R, 5R, 6aS)-octahydro-5-hydrox y-4-[(E)(3S, 5S)-3hydroxy-5-methyl-1-nonenyl]-2-pentalenyl] ethoxy] ac etate (SM-10902, CAS 139403-31-9), a novel stable analogue of prostacy clin and its free acid, SM-10906, were studied. SM-10902 was rapidly d eesterified to its free acid in rabbit and human serum. SM-10902 and S M-10906 exhibited antiplatelet potency against ADP-induced aggregation in rabbit and human platelets. In the presence of diisopropyl fluorop hosphate, an esterase inhibitor the antiplatelet activity ofSM-10902 w as markedly reduced, to much less than that of SM-10906. SM-10906 inhi bited platelet aggregation induced by various inducers in several spec ies and enhanced the cyclic AMP (cAMP) level in human platelets. These activities were nearly equal to those of prostaglandin (PG) E(1) and less than those ofPGI(2). SM-10906 relaxed isolated rabbit mesenteric and bovine coronary arteries, and elevated the cAMP level in bovine co ronary arteries. SM-10906 given intravenously exhibited a sustained re duction in blood pressure based on vasodilation in ganglion-blocked, a ngiotensin II-supported rats. SM-10902 applied to the guinea-pig auric les increased the skin temperature, but SM-10906 and PGI(2) showed no such effect. In conclusion, SM-10902, which is consider ed to be a pro drug of SM-10906, was suggested to exert its antiplatelet and vasodila tor activities through the increase of cAMP. Since SM-10902 penetrates well into the skin, it may be useful as an external preparation to im prove peripheral circulatory insufficiency.