Affinity for [³H]Iloprost Binding Sites and cAMP Synthesis Activity of a 3-Oxa-methano Prostaglandin I₁ Analog, SM-10906, in Human Platelets and Endothelial Cells

Abstract

SM-10902 ((+)-methyl [2-[(2R, 3aS, 4R, 5R, 6aS)-octahydro-5-hydroxy-4-[(E)-(3S, 5S)-3-hydroxy-5-methyl-1-nonenyl]-2-pentalenyl]ethoxy]acetate)and its free acid, SM-10906 are new stable 3-oxamethano prostaglandin (PG)I₁ analogs. Their affinities for [³H]iloprost and [³H]PGE₂ binding sites in human platelets and human umbilical vascular endothelial cells were compared with those of the PGI₂ analog iloprost, PGE₁ and PGE₂ by the radioligand binding assay method. The cyclic AMP (cAMP)synthesis activity of these drugs were also determined in human umbilical vascular endothelial cells. We found that SM-10906 apparently displaced [³H]iloprost binding to the membrane fractions in those cells since the pK_i values were 6.30 in platelets, 7.52 in vein endothelial cells and 6.31 in the arterial endothelial cells. The pK_i values of SM-10906 for [³H]PGE₂ binding sites were significantly lower than those obtained for [³H]iloprost binding. SM-10902, which is a prodrug of SM-10906, showed low affinity for [³H]iloprost binding sites in those cells. SM-10906 also dose-dependently enhanced the cAMP level in the vascular endothelial cells. Thus, these findings indicate that SM-10906 binds to [³H]iloprost binding sites and exhibits pharmacological functions such as an anti-platelet action and a cytoprotective action in endothelial cells through the elevation of intracellular cAMP contents.