TEI-3356, A HIGHLY SELECTIVE AGONIST FOR THE PROSTAGLANDIN EP3 RECEPTOR

Recently, we cloned cDNAs for the three mouse PGE receptor subtypes, E P1, EP2 and EP3, and the prostacyclin receptor, and established cells that stably express each receptor. We examined the selectivity of TEI- 3356, an isocarbacyclin analogue, compared with other EP agonists, sul prostone and misoprostol, using Chinese hamster ovary cells expressing each cloned receptor. TEI-3356 selectively displaced the [H-3]PGE(2) binding to EP3-expressing cell membranes, but showed very low affinity for both EP1 and EP2. Although TEI-3356 is an isocarbacyclin analogue , it showed low affinity for the prostacyclin receptor. On the other h and, sulprostone strongly displaced the [H-3]PGE(2), binding to EPI an d EP3, but not to EP2. Misoprostol weakly bound to the three subtypes without selectivity. TEI-3356 decreased the forskolin-induced cAMP for mation in a concentration-dependent manner in the EP3 expressing cells , the half-maximal concentration for the inhibition being similar to t hat of sulprostone but lower than that of PGE(2). These results demons trate that TEI-3356 is a potent and highly selective agonist for the E P3 receptor.