内皮素-1受体拮抗剂的筛选和药理学研究

Screening of ET-1 receptor antagonists and the pharmacological evaluation

目的对军事医学科学院毒物药物研究所合成的系列内皮素受体拮抗剂进行筛选,并对有效化合物进行抗肺动脉高压的药理学研究。方法放射配体-受体结合实验测定受试化合物对ETA和ETB受体亚型的亲和力;在ET-1诱发离体大鼠主动脉环收缩、整体大鼠颈动脉压升高实验模型上进行生物活性筛选;在野百合碱诱发大鼠肺动脉高压实验模型上对受试化合物进行抗肺动脉高压的药效学研究。结果部分化合物与ETA受体的亲和力比与ETB受体的亲和力高万倍以上,并能有效地抑制ET-1诱发的离体大鼠主动脉环收缩,其中1μmol.L-1的受试化合物ETP-508可使ET-1累加浓度收缩效应曲线平行右移,且最大效应不变。此外,3.7μg.(0.5ml)-1.kg-1ET-1所致的大鼠体动脉压升高也可被2mg·kg-1ETP-508等化合物静脉注射所阻断;更进一步,ETP-508和BQ-485静脉给药(0.4mg.h-1)还可逆转80mg·kg-1野百合碱皮下一次注射诱发的大鼠肺动脉高压。结论以上结果提示,ETP-508和BQ-485是高选择性的ETA受体竞争性拮抗剂,能有效地抑制野百合碱诱发的大鼠肺动脉高压。

Aim Series of compounds, which were considered to be the antagonists of ET-1 receptor,were synthesized by Beijing Institute of Pharmacology and Toxicology. The biological activity of these compounds was screened and some active compounds were selected for further pharmacological characterization on pulmonary hypertension. Methods Radioligand binding assay was performed to study the binding affinity of compounds for ETA and ETB receptors. The biological activity of compounds was evaluated in isolated rat aortic ring and in systemic arterial pressure （SAP） of anesthetized rat experiments. In addition, hypotensive effect of compounds was investigated on monocrotaline induced pulmonary hypertension in rats. Results Compounds bind to ETA receptor had over 10 000 fold higher affinity than to ETB receptor. Contraction induced byET-1 in isolated rat aortic ring was inhibited by compounds, and 1μmol · L^-1 ETP-508 shifted the cumula- tive concentration-contraction response curve to ET-1 to right with no change in the maximal response. In vivo, the increase in SAP induced by ET-1 [ 3.7 μg · （0.5 ml）^-1 . kg^-1] was inhibited by 2 mg· kg^-1 compounds by intravenous infusion. Furthermore, BQ-485 and ETP-508 by intravenous infusion （0. 4 mg ·h^-1 ） significantly inhibited 80 mg · kg ^- 1 （sc） monocrotaline induced pulmonary hypertension in rats. Conclusions These results indicate that ETP-508 and BQ-485 are highly selective ETA receptor antagonists and cantly inhibite monocrotaline induced pulmonary tension in rats. signifihypertension in rats.