內皮素受體拮抗劑於調節血壓研究之進展

Recent Development of Endothelin Receptor Antagonists for the Modulation of Blood Pressure

楊志展(Chih-Ping Yang) ； 黃雪莉(Shir-Ly Huang)

《化學》 52卷4期 (1994/12) Pp. 454-461

https://doi.org/10.6623/chem.1994058

摘要

內皮素(endothelin. ET)是由21個胺基酸組成，具有血管收縮活性之胜肽，目前已知的三種不同內皮素分別為ET-1、ET-2和ET-3。由內皮素引起的生理反應，分別由三類受體調控：ET_A、ET_B，和ET_C。當內皮素與其ET_A受體結合，經由兩種細胞訊息傳遞系統導致血壓昇高。內皮素受體拮抗劑被認為具有降低血壓的治療效果，目前已有許多高活性的拮抗劑被發現，其中以Hoffman-La Roche公司研發的Ro 47-0203 (Bosentan)為代表，此一藥物目前已進行第一期人體臨床試驗。具高生體可用率且分子量較小內皮素受體拮抗劑的發現，不但可以增進我們對於內皮素生理機能的瞭解，並且可應用於高血壓及其它心血管疾病的治療。

並列摘要

The discovery of endothelin-1 (ET-1), a potent 21-amino acid vasoconstrictor, from the cultured porcine endothelial cells was first reported in 1988 by Yanagisawa. It is now considered that there are three distinct genes encoding the isopeptides of endothelin, ET-1, ET-2, and ET-3, in mammalian genome. Since three distinct types of pharmacological responses among three ETs have been observed in a variety of biological systems, the pharmacological responses induced by endothelin peptides may he mediated by at least three subtypes of receptor, namely ET_A, ET_B and ET_C. ET-induced vasoconstriction has been demonstraled to be mediated through two intracellular signal transduction systems: phos-pholipase C activation and opening of voltage-dependent L- type calcium channel. Numerous reports have described the effects of ET on the cardiovascular system. Recently, several competitive ET receptor antagonists have been reported. They exhibit potent antagonistic activities, IC_(50) values range from 0.1 to 100 nM. Among them, Ro 47-0203 (Bosentan); is currently in phase I clinical trials. The discovery of bioavailable samll molecule ET antagonists should provide better understanding of the physiological role of ET and also provide potential therapeutical agents for the unmet medical needs in the treatment of human hypertension.