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.
Mihara
S
S
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Sakurai
K
K
Nakamura
M
M
Konoike
T
T
Fujimoto
M
M
D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007457:Iodine Radioisotopes; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D017466:Receptors, Endothelin / Q000187:drug effects; D013329:Structure-Activity Relationship
D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007457:Iodine Radioisotopes; D017466:Receptors, Endothelin; C075745:myriceron caffeoyl ester; D002118:Calcium