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Studies on Structure Diuretic Activity Relationships of Organic Compounds of Mercury

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Studies on Structure Diuretic Activity Relationships of Organic Compounds of Mercury STUDIES ON STRUCTURE DIURETIC ACTIVITY RELATIONSHIPS OF ORGANIC COMPOUNDS OF MERCURY R. H. Kessler, … , R. Lozano, R. F. Pitts J Clin Invest. 1957;36(5):656-668. https://doi.org/10.1172/JCI103466. Research Article Find the latest version: https://jci.me/103466/pdf STUDIES ON STRUCTURE DIURETIC ACTIVITY RELATIONSHIPS OF ORGANIC COMPOUNDS OF MERCURY' By R. H. KESSLER,2 R. LOZANO,3 AND R. F. PITTS (From Thc Department of Physiology, Cornell University Mledical Collcgc, Neczw York, N. Y.) (Submitted for publication December 3, 1956; accepted January 10, 1957) The mercurial diuretics in commiiiion use today are available or easily prepared as starting ma- exhibit certain basic similarities in structure. All terials. Mercuration in methyl alcohol is relatively are mercurated derivatives of substituted three easy and yields of the 3-mercuri-2-methoxy propyl carbon compounds of the type indicated below, in end products are satisfactory. Logical questions which the three substituents are designated X, OY, which arise include: Is the three carbon side chain and R. of the presently used diuretics an essential or opti- H H H mal element of diuretic structure, or is it merely a matter of preparative convenience? X-Hg-C-C-C(-R The diuretic activity of organic mercurial com- of HOY H pounds has recently been ascribed to inhibition sulfhydryl enzymes concerned with the renal tu- According to Friedman ( 1 ), the nature of the X blular reabsorption of sodium and chloride ions substituent (usually halogen, theophylline or thio- (2, 3). Mercuric chloride and certain relatively glycolate) has no effect on diuretic potency if the simple organo-mercurials, including bromomer- compound is given intravenously, but does influ- curi-methane, bromo-mercuri-benzene and para- ence both hyperacute (cardiac and respiratory chloromercuri-benzoate, are potent and more or arrest) and acute (7 to 14-day) renal toxicity. less specific inhibitors of sulfhydryl enzymes in The nature of the OY group is determined by the vitro (4, 5). Are these compounds also diuretics solvent in which the mercuration is carried out and are their diuretic activities in any way related and is an hydroxyl group, if the solvent is water. to their activities as enzyme inhibitors? or a methoxy or ethoxy group, if the solvent is the Mercuhydring (6, 7) and Neohydring (8, 9) corresponding alcohol. Within these limits, i.e., have been shown to disappear rapidly from the OH, OCH3, or OC.,H5, the nature of the OY blood stream following intravenous administration group is without appreciable effect on either diuretic and to accumulate in the renal cortex in high potency or toxicity. In contrast, the nature of the concentration. Both drugs are highly bound to R group, which is commonly rather complex, has plasma proteins, hence are sparingly filtered a very great effect on both toxicity and diuretic through the glomerular capillaries, yet both are activity. In the diuretic mersalyl, R is o-carbamyl- rapidly eliminated in the urine. Accordingly, tu- phenoxyacetic acid; in mercaptomerin, R is cam- bular secretion must play a role in their excretion. phoramic acid; in meralluride, R is succinyl-urea; Is rate of removal from plasma, rapidity of up- in chlormerodrin, R is urea; and in mercumatilin, take by the renal cortex or rate of secretion by the R is coumarin. Much of the interest in the struc- renal tubules correlated with diuretic activity ? ture-activity relationships of mercurial compounds The present study was undertaken to answer has centered around the effects of modification of the three questions posed above: (a) is the three R and relatively less attention has been paid to carbon side chain essential for diuretic action; (b) simple organo-mercurial compounds. are sulfhydryl enzyme inhibitors necessarily diu- be related to A wide variety of substituted allyl compounds retics; and (c) can diuretic activity distribution and fate of the mercurial compound in 1 Aided by grants from the National Heart Institute, the body. Twelve organic compounds of mercury National Institutes of Health and the Life Insurance Medi- and the single inorganic compound, mercuric Research Fund. cal our 2 Fellow of the Life Insurance Medical Research Fund. chloride, were synthesized in laboratory using 3 Fellow of the Rockefeller Foundation. Hg203 as a label. Each compound was adminis- 656 STRUCTURE-ACTIVITY RELATIONSHIPS OF MERCURIAL COMPOUNDS 657 tered intravenously to anesthetized dogs in doses We are indebted to Dr. H. L. Friedman of Lakeside of 1, 2, and 4 mg. of mercury per kilo of body Laboratories, Inc. for directions for the preparation of chlormerodrin and meralluride and also for a supply of weight. In all, over 50 experiments have been per- both the allylurea and the succinylallylurea used as start- formed on an equal number of dogs. All experi- ing materials. We are similarly indebted to Dr. C. M. ments were acute for it was necessary to sacrifice Suter, of the Sterling-Winthrop Research Institute for each animal in order to obtain tissue samples. If advice on the preparation of mersalyl and for a supply one disregards mercuric chloride, which is moder- of o-allylcarbamyl-phenoxyacetic acid. The remainder of the syntheses were taken from the literature and the as a structure we ately effective diuretic, the which appropriate references are noted in Table I. have observed to be associated with diuretic ac- All syntheses were performed several times with non- tivity includes (a) a chain of not less than 3 car- radioactive mercury prior to a radioactive run. Struc- bon atoms, (b) an atom of mercury attached to the tures of end products were not proved. However, cri- terminal carbon of this chain and (c) some hydro- teria of adequacy of preparation included reproducibility of product, melting point, solubility characteristics and group from philic not less than 3 carbons distant gravimetric mercury analysis as the sulfide. Brief de- the mercury. Probably other structures are com- scriptions of these characteristics of the compounds syn- patible with diuretic activity; however, many are thesized are included in Table I. not. All mercurial compounds are concentrated Chemical procedures employed in the analyses of blood, to some degree in the renal cortex, yet the degree urine and tissue samples are those described in a previ- ous communication (9). of concentration seems but little related to diuretic potency. Those compounds which are very slowly Biological excreted have no diuretic activity whereas those With one exception,4 identical procedures were fol- which are most rapidly excreted are, with one ex- lowed in all experiments. All were performed on fe- ception, diuretics. However, this exception is male mongrel dogs, anesthetized with not more than 30 sufficiently striking to discourage attaching great mg. of pentobarbital per kilo intravenously, supplemented significance to a correlation of urinary mercury as needed. Following anesthesia, one liter of 0.85 per cent excretion and diuretic potency. Finally, three of saline was administered intravenously, a priming dose of creatinine was given and an infusion of creatinine in the compounds most widely used as inhibitors of saline was begun at a rate of 2 cc. per minute. The left sulfhydryl enzymes in vitro are without diuretic kidney was exteriorized through a 5-cm. flank incision and activity. Thus, if diuresis is related to inhibition held in contact with an end window Geiger tube by a of sulfhydryl enzymes, the inhibitors must have sheet of rubber dam perforated to pass the renal pedicle. properties other than, or structures different from A film of Saran plastic separated the kidney from the Geiger tube to protect the latter from contamination. those of bromomercuri-methane, bromomercuri- Counts were recorded every minute and represent semi- benzene and p-chloromercuri-benzoate. quantitatively variations in the concentration of radio- mercury in the outer few millimeters of the renal cortex. METHODS When urine flow stabilized, two 20-minute control clear- ance periods were obtained. Blood samples were drawn Chemical through a retention needle in the femoral artery, urine All syntheses were performed in our laboratory start- was collected with a Foley catheter and the bladder was ing with the radioisotope Hg'O. As shipped from Oak washed out with 10 cc. of distilled water at the end of Ridge National Laboratories, this product contains 3 each urine collection period. curies of Hg"T per irradiation unit, with a half life of 2.71 The mercury compound, dissolved with a minimum of days. To avoid using material of high and rapidly alkali or alcohol, if the solubility was greater in the changing activity, the isotopic mixture was allowed to latter solvent, was administered intravenously in 20 sec- stand for two weeks or more prior to use. The isotope onds following the second control clearance period. Each Hg' has a half life of 43.5 days and emits beta particles compound was given in three experiments in doses of 1, of 0.205 MEV. and gamma rays of 0.286 MEV. When 2 and 4 mg. mercury per kilo body weight. Arterial first used, the organic mercurial compounds counted at a blood samples were drawn 1, 2, 3, 5, 7, 10 and 15 minutes rate of approximately 4,000 per minute per microgram of after the start of the mercury injection and thereafter mercury in a well-type scintillation unit. They were used for two or at most three half life periods; some required 4In this experiment, designed to test the effects of recrystallization one or more times during this interval Probenecid@ on the secretion of p-chloromercuri-ben- because of decomposition with liberation of metallic mer- zoate, the mercurial compound was infused intravenously cury, which strangely did not occur with the non-radio- throughout the course of the experiment instead of being active compounds nor with all of the radioactive ones.
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