Objective: To investigate the endothelin-antagonizing effects of a series of the novel derivatives of diphenylpropionic acid. Methods: Intracellular calcium assay ( FLIPR ) was performed to assess the effects of compounds on endotheline-1 ( ET-1 ) -activated calcium mobilization in CHO cells expressing recombinant human ETA receptor ( rhETA). Among these derivatives, some active compounds were selected to further assess the pharmacological effects on ET-1-induced contraction in isolated rat aortic rings, and systemic arterial pressure in rats. Results: The increase of intracellular calcium stimulated by ET-1 in rhETA CHO cells was remarkably inhibited by nine compounds including TY6089 and TY60841. In isolated rat aortic rings, ET-1 (1×l0-8 mol· L-1)-induced vasoconstriction was significantly antagonized by TY6089 and TY60841. In vivo, the increase of mean arterial pressure (MAP) was inhibited by TY6089 and TY60841 , and the effects were dose-dependent in the range of 15~60 mg·kg-1. Conclusion: The novel derivatives of diphenylpropionic acid TY6089 and TY60841 exhibit potent ET-1-antagonizing effects, and are worthy of further investigation.%目的:考察新型丙酸衍生物的内皮素拮抗作用.方法:采用FLIPR(R)钙分析法检测化合物对内皮素-1(endothelin-1,ET-1)激活高表达内皮素受体的CHO细胞内钙升高的抑制作用；采用ET-1诱导的血管环收缩和大鼠血压升高模型进一步考察受试化合物的活性.结果:9个丙酸衍生物(包括TY6089和TY60841)能有效抑制ET-1所激发的细胞内钙升高,可有效抑制ET-1(1×10-8 mol· L-1)所诱导的大鼠离体血管环收缩.15～60mg·kg-1剂量范围的TY6089和TY60841可有效抑制ET-1诱导的大鼠平均动脉压(mean arterial pressure,MAP)升高,并呈剂量依赖性.结论:新型丙酸衍生物TY6089和TY60841有良好的内皮素拮抗作用,值得进一步深入研究.
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