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As the first non-peptide endothelin receptor antagonist from a higher plant, a new triterpenoid, myriceric acid A (50-235) (1) was isolated from the bayberry, Myrica cerifera. Myriceric acid A (1) inhibited not only an endothelin-1-induced increase in cytosolic free Ca2+ concentration (IC50 = 11 +/- 2 nM) but [125I]endothelin-1 binding in rat aortic smooth muscle cells (Ki = 66 +/- 15 nM). Two new related triterpenoids, myriceric acid C (6), and myriceric acid D (8), were also isolated. Furthermore, the chemical modification of these natural products led to the synthesis of sulfated derivatives (13, 14, 15) which showed 1.5 to 20 times higher affinity for endothelin receptors. The structure activity relationships of myriceric acids and their derivatives are discussed.

A potent non-peptide ET receptor antngonisl, myriceron caffeoyl ester (50-235), was isolated from the bayberry, ,44yrica ccr~$m~. This compound selectively antagonized specific binding of ["'IlET-I, but not of [lz51]ET-3, to rnt cardiac membranes, ET-L-indud increase in the intracellular free calcium concentration in Swiss 3T3 fibroblasts. and ET-l-induced contraction of rat aortic strips. Thus, 50-235 is the first non-peptide ET,, receptor antagonist. This compound cnn be useful for studying the physiological role of cndothclin and exploring its role in various diseases.

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