Screening of ET-1 receptor antagonists and the pharmacological evaluation / 中国药理学通报

ABSTRACT

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 by ET-1 in isolated rat aortic ring was inhibited by compounds,and 1 ?mol?L-1 ETP-508 shifted the cumulative 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 ?g?(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 significantly inhibite monocrotaline induced pulmonary hypertension in rats.