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 ET(A) 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 it s derivatives to inhibit [I-125]endothelin-1 binding and endothelin-1- induced increase in the cytosolic Ca2+ concentration in rat aortic smo oth muscle A7r5 cells. The results suggest that the 3-keto, 17-carboxy l and 27-caffeoyl groups in 50-235 are important for ET(A) receptor bl ocking 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.