Prostacyclin (PGI) receptor binding and cyclic AMP synthesis activities of PGI1 analogues, SM-10906 and its methyl ester, SM-10902, in mastocytoma P-815 cells.
The prostacyclin I1 (PGI1) analogue, SM-10906 and its methyl ester, SM-10902, have been compared with the PGI2 analogue, iloprost, with respect to binding to the PGI2 receptor, stimulation of adenylate cyclase activity and inhibition of thrombin-induced Ca2+ mobilization in mastocytoma P-815 cells. SM-10906 displaced [3H]iloprost binding to the membrane fraction, the IC50 value being 100 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 EC50 value being 35 nM. Furthermore, SM-10906 prevented a thrombin-induced increase in the intracellular Ca2+ concentration, the IC50 value being 300 nM. These IC50 and EC50 values are much lower than those of SM-10902. These results demonstrate that SM-10906, a stable PGI1 derivative, is an agonist for the [3H]iloprost-binding (PGI2) receptor, and that it prevents thrombin-induced Ca2+ mobilization through stimulation of the adenylate cyclase system in mastocytoma cells. On the other hand, a methyl ester derivative of PGI1, SM-10902, was inactive in the binding assay, but it seems to be a partial agonist for adenylate cyclase activity [corrected].
Oka
M
M
Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Negishi
M
M
Yamamoto
T
T
Satoh
K
K
Hirohashi
T
T
Ichikawa
A
A
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016285:Iloprost / Q000378:metabolism / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D012515:Mast-Cell Sarcoma; D051379:Mice; D011458:Prostaglandins E / Q000378:metabolism; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D011458:Prostaglandins E; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; C086699:SM 10906; C086698:SM 10902; D011464:Epoprostenol; D000242:Cyclic AMP; D013917:Thrombin; D000262:Adenylyl Cyclases; D016285:Iloprost; D002118:Calcium