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目的:考察新型丙酸衍生物的内皮素拮抗作用。方法:采用FLIPR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(1×10-8mol.L-1)所诱导的大鼠离体血管环收缩。15～60 mg.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。
Objective: To investigate the endothelin antagonism of novel propionic acid derivatives. Methods: The inhibitory effect of compounds on endothelin-1-overexpressing intracellular calcium in endothelin-1 (ET-1) -induced CHO cells was detected by FLIPR calcium assay. Contractions and rat models of elevated blood pressure further examined the activity of the test compound. Results: Nine derivatives of propionic acid, including TY6089 and TY60841, were able to effectively inhibit the intracellular calcium elevation induced by ET-1 and effectively inhibit the large induced by ET-1 (1 × 10-8 mol·L-1) Rat isolated vascular ring contraction. TY6089 and TY60841 in the dose range of 15 ~ 60 mg.kg-1 effectively inhibited the ET-1-induced increase of mean arterial pressure (MAP) in a dose-dependent manner in rats. Conclusion: The new propionic acid derivative TY6089 and TY60841 have good antagonism of endothelin, which deserves further study.