title: TEI-9063, a stable and highly specific prostacyclin analogue for the prostacyclin receptor in mastocytoma P-815 cells.
abstract: The prostacyclin (PGI2) analogues, TEI-9063 and its methyl ester, TEI-1324, have been compared with another stable 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. TEI-9063 displaced the [3H]iloprost binding to the membrane fraction, the IC50 value being 3 nM, but showed very low affinity for the PGE receptor. TEI-9063 dose dependently stimulated cAMP formation in the cells and GTP-dependent adenylate cyclase activity in the membrane fraction, the EC50 value being 50 and 10 nM, respectively. Furthermore, TEI-9063 prevented the thrombin-induced increase in the intracellular Ca2+ concentration, the IC50 value being 50 nM. These IC50 and EC50 values are lower than those obtained for iloprost. On the other hand, those of TEI-1324 were about two-orders higher. Although PGI2 lost its ability to stimulate cAMP formation by preincubation for 20 min at 37 degrees C, TEI-9063 completely retained its ability after 60-min preincubation. These results demonstrate that TEI-9063 is a stable and stronger agonist for the PGI2 receptor than iloprost, and that it prevents thrombin-induced Ca2+ mobilization through stimulation of the adenylate cyclase system in mastocytoma cells.
authors.affiliation: Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Negishi
authors.forename: H
authors.initials: H
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Yatsunami
authors.forename: S
authors.initials: S
authors.lastname: Kurozumi
authors.forename: A
authors.initials: A
authors.lastname: Ichikawa
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D016285:Iloprost / Q000494:pharmacology; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C057340:17,20-dimethylisocarbacyclin; D006160:Guanosine Triphosphate; D011464:Epoprostenol; D000262:Adenylyl Cyclases; D016285:Iloprost; D002118:Calcium