628 Journal of Medicinal Chemistry, 1971, Vol. 14,No. 7
NOTES
as calcd from the common regression line derived from probit analysis of the cumulative dose-response curves. The dose (1.84 x 10-4 M ) and exposure time (20 min) of phenoxybenzamine were the same as used by Winter and G e ~ s n e r . ~ Rabbit rectal temp measurements were made with Cu-constantin thermocouples on old male rabbits as described by Brimblecombe. 10
tion, the carcinogenicity of many epoxides is thought to be due to their reaction with various nucleophilic groups (i.~.,SH, NH?) of We reasoned that if a reaction with PBSH in rend tissue is necessary for the diuretic action of ethacryriic acid, then the epoxide 2a could conceivably alkylate (by an Ssl! reaction) these essential groups and act either as a diuretic agent or ab an antagonist of the diuretic action of ethacrynic acid. Synthesis and Pharmacology of a n Epoxide Ethacrynic acid and its epoxide derivative 2a were Derivative of Ethacrynic Acid compared on the basis of their diuretic activity, renal S a + - and K i - *2TI'ase inhibitory activity, and an titro DANIELA . KOECHEL,*l OLE GISVOLD, reactivity uith cysteine. The epoxide 2a failed to inDepartment of Medicinal Chemistry, duce a measurable diuretic response in dogs when adCollege of Pharmacy, Universily of Minnesota, ministered iv in a dose of 2 mg/kg. The method of Minneapolis, Minnesota 55455 testing was similar to that used hy Small arid Cafruny. l 4 Even when the iv dose of 2a ivaz increased to 23 mg/kg, A N D EDWARD J. CAFRUNY there was no significant diuretic effect. Urine flow was Department of Pharmacology and Therapeutics, monitored for 30 min ttfter administration of 2a. The Medical College of Ohio, Toledo, Ohio 49614 glomerular filtration rate, measured as t hc rerial clearance of inulin, \\ as not affected. When injected diReceived September 3, 1970 rectly into tubular lumens by the retrograde intraluniinal injection technique1i the epoxide failed to elicit a Ethacrynic acid (1) is thought to evoke a diuretic diuretic reiponbe j3.5 nil of an aq niannitol d i (2Ooc;I response by reacting with protein-bound sulfhydryl wt 'wt) containing 10 mg of tlie epoxide 'ml]. >2n1v groups (PBSH) in renal tubular cells.2-6 I t has been suggested that a Michael-type reaction is i n ~ o l v e d . ~ dose of 2a ( 2 or 25 mg/'kg) 30-niin prior to iv adminibtration of ethacrynic acid (2.0 mg 'kg) failed to antagoIn an attempt to explore this hypothesis further, we nize the normal diuretic respon5e t o the latter agent have synthesized the epoxide derivative 2a of ethacrynic Canine renal S a + -and I
