Koechel D A, Cafruny E J
J Pharmacol Exp Ther. 1975 Jan;192(1):179-94.
It is thought that a derivative of ethacrynic acid (EA) must possess an intact alpha, beta-unsaturated ketone group in order to be capable of eliciting a diuretic response. The 2,3-dimercapto-1-propanol and the cysteine adducts of ethacrynic acid lack such a functional group and still have diuretic activity, especially the cysteine adduct. An in vitro study showed that various thiol adducts of EA liberate EA and the accompanying thiol at a rate that is primarily dependent on the nature of the functional groups present in the thiol portion of the adduct. When the thiol adducts of EA were injected into dogs, the cysteine and mercaptoethylamine hydrochloride adducts which rapidly release EA under specific in vitro conditions were as effective as EA in producing a diuretic response. The onset of action was also similar to that of EA. The thiosalicylic acid adduct of EA releases the accompanying thiol at an intermediate rate in vitro and was less effective than EA in a small dose (3.3 mumol/kg) and the peak response to it was slower to develop. Other adducts that release EA and the accompanying thiol slowly in vitro either produce a very weak response which takes considerable time to develop or are completely devoid of diuretic activity. Thus, the onset and magnitude of the diuretic response produced by various thiol adducts of EA (with the possible exception of the cysteine adduct) are governed primarily by the rate of in vivo release of EA.
据认为，依他尼酸（EA）的衍生物必须具有完整的α，β-不饱和酮基团才能引发利尿反应。依他尼酸的2,3-二巯基-1-丙醇和半胱氨酸加合物缺乏这样的官能团，但仍具有利尿活性，尤其是半胱氨酸加合物。一项体外研究表明，EA的各种硫醇加合物释放EA和伴随硫醇的速率主要取决于加合物硫醇部分中存在的官能团的性质。当将EA的硫醇加合物注射到狗体内时，在特定体外条件下能快速释放EA的半胱氨酸和巯基乙胺盐酸盐加合物在产生利尿反应方面与EA一样有效。起效时间也与EA相似。EA的硫代水杨酸加合物在体外以中等速率释放伴随的硫醇，在小剂量（3.3 μmol/kg）时比EA效果差，对其的峰值反应发展较慢。其他在体外缓慢释放EA和伴随硫醇的加合物要么产生非常微弱的反应，需要相当长的时间才能发展，要么完全没有利尿活性
