Structure-activity relationships of an endothelin ETA receptor antagonist, 50-235, and its derivatives

27-O-Caffeoyl myricerone (50-235) is a nonpeptide endothelin receptor antagonist which is highly selective for the endothelin ETA receptor subtype. In order to determine which functional groups in 50-235 are essential for its activity, we examined the potencies of 50-235 and its derivatives to inhibit [125I]endothelin-1 binding and endothelin-1-induced increase in the cytosolic Ca2+ concentration in rat aortic smooth muscle A7r5 cells. The results suggest that the 3-keto, 17-carboxyl and 27-caffeoyl groups in 50-235 are important for ETA receptor blocking activity. Modifications of the catechol ring of the 27-caffeoyl group influenced the affinity and the functional antagonist activity, but the effects were not parallel.