Takashi Hiroi (1), Keiko Maruyama (1), Kaoru Hattori (1), Toshio Ohnuki (1), Takafumi Nagatomo (1,*), Kenichi Watanabe (2), Takaaki Yamamoto (3) and Youichi Hara (3)
(1) Department of Pharmacology, Niigata College of Pharmacy, 5-13-2
Kamishinei-cho, Niigata 950-21, Japan
(2) Cardiovascular Division, Tsubame Rosai Hospital, Tsubame, Niigata 959-12,
Japan
(3) Research Center, Sumitomo Pharmaceutical Co., Ltd., 1-98, Kasugade Naka
3-Chome, Konohana-ku, Osaka 554, Japan
(*) To whom correspondence should be addressed.
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-oxa-methano 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 pKi values were 6.30 in platelets, 7.52 in vein endothelial cells and 6.31 in the arterial endothelial cells. The pKi 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.
Keywords: [3H]Iloprost binding site, Cyclic AMP, SM-10906, Endothelial cell, Platelet