Thiol adducts of ethacrynic acid: a correlation of the rate of liberation of ethacrynic acid with the onset and magnitude of the diuretic response.
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.
D000704:Analysis of Variance; D000818:Animals; D001711:Biotransformation; D002712:Chlorides / Q000652:urine; D003545:Cysteine / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004976:Ethacrynic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D008297:Male; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000652:urine; D013438:Sulfhydryl Compounds; D013440:Sulfides / Q000494:pharmacology; D013997:Time Factors
D002712:Chlorides; D013438:Sulfhydryl Compounds; D013440:Sulfides; D012964:Sodium; D003545:Cysteine; D004976:Ethacrynic Acid; D011188:Potassium