Prostacyclin (PGI) Receptor Binding and Cyclic AMP Synthesis Activities of PGI_1 Analogues, SM-10906 and Its Methyl Ester, SM-10902,in Mastocytoma P-815 Cells

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The prostacyclin I_1 (PGI_1) analogue, SM-10906 and its methyl ester, SM-10902,have been compared with the PGI_2 analogue, iloprost, with respect to binding to the PGI_2 receptor, stimulation of adenylate cyclase activity and inhibition of thrombin-induced Ca^<2+> mobilization in mastocytoma P-815 cells. SM-10906 displaced [^3H]iloprost binding to the membrane fraction, the IC_<50> value being 20 nM, but showed very low affinity for the prostaglandin E (PGE) receptor. SM-10906 dose-dependently stimulated GTP-dependent adenylate cyclase activity in the membrane fraction, the EC_<50> value being 35 nM. Furthermore, SM-10906 prevented a thrombin-induced increase in the intracellular Ca^<2+> concentration, the IC_<50> value being 100 nM. These IC_<50> and EC_<50> values are much lower than those of SM-10902. These results demonstrate that SM-10906,a stable PGI_1 derivative, is an agonist for the [^3H]iloprost-binding (PGI_2) receptor, and that it prevents thrombin-induced Ca^<2+> mobilization through stimulation of the adenylate cyclase system in mastocytoma cells. On the other hand, a methyl ester derivative of PGI_1,SM-10902,was inactive in the binding assay, but it seems to be a partial agonist for adenylate cyclase activity.
社団法人日本薬学会の論文
1994-01-15