Synthesis and Diuretic Activity of Alkyl- and Arylguanidine Analogs of N,N'-Dicyclohexyl-4-morpholinecarboxamidine in Rats and Dogs

Perricone, Sam C.; Humphrey, Stephen J.; Skaletzky, L. L.; Graham, Boyd E.; Zandt, Ralph A.; Zins, Gerald R.

doi:10.1021/jm00048a005

Cited by 20 publications

(16 citation statements)

References 7 publications

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“…2, acute i.v. PNU-18177A unexpectedly reversed minoxidil's arterial hypotension in conscious dogs, suggesting direct antagonism of the latter's peripheral vasodilation (91). A similar vascular interaction was subsequently confirmed with PNU-37883A, which reversed the effects of minoxidil in anesthetized cats (Fig.…”

Section: Chemistry and Initial Detection Of Biological Activitysupporting

confidence: 57%

“…In conscious rats, PNU-37883A (10 to 100 mg/kg p.o.) increased urinary volume and Na + exertion two-to sixfold without the kaliuresis seen with hydrochlorothiazide and furosemide or the K + retention common to amiloride and triamterene (91). A similar two-to 10-fold eukalemic natriuresis was also seen in conscious dogs with i.v.…”

Section: Diuretic Activity In Rats and Dogsmentioning

confidence: 74%

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Pharmacology of the K‐ATP Channel Blocking Morpholinoguanidine PNU‐37883A

Humphrey

1999

Cardiovascular Drug Reviews

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Section: Chemistry and Initial Detection Of Biological Activitysupporting

confidence: 57%

Section: Diuretic Activity In Rats and Dogsmentioning

confidence: 74%

Pharmacology of the K‐ATP Channel Blocking Morpholinoguanidine PNU‐37883A

Humphrey

1999

Cardiovascular Drug Reviews

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“…porter, resulting in natriuresis (26)(27)(28). Other compounds that also ostensibly produce natriuresis via inhibition of K+ channels have been described; however, LLU-a is the most potent inhibitor yet reported (29)(30)(31), with an ID50 of about 5 nM.…”

Section: Discussionmentioning

confidence: 99%

A new endogenous natriuretic factor: LLU-alpha.

Wechter

Kantoci

Murray

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

181

126

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For over three decades, renal physiology has sought a putative natriuretic hormone (third factor) that might control the body's pool of extracellular fluid, an important determinant in hypertension, congestive heart failure, and cirrhosis. In our search for this hormone, we have isolated several pure natriuretic factors from human uremic urine that would appear, alone or in combination, to mark a cluster of phenomena previously presumed to be that of a single "natriuretic hormone." This paper reports the purification, chemical structure, and total synthesis of the first of these compounds, LLU-a, which proved to be 2,7,8-trimethyl-2-(pcarboxyethyl)-6-hydroxychroman, presumably a metabolite of y-tocopherol. Both natural LLU-a and synthetic material are identical (except for optical activity) with respect to structure and biological activity. It appears that the natriuretic activity of LLU-a is mediated by inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the kidney.As a result of salt-induced plasma-volume expansion in mammals, three concurrent events have been observed: sustained natriuresis, rising plasma concentration of a Na+ transport inhibitor, and pressor activity. It has been presumed that these effects are due to elaboration of a low-molecular-weight "natriuretic hormone," the putative controller of extracellular fluid (1). Over 30 years of effort have failed to characterize the putative hormone (2, 3). Atrial natriuretic factor, when infused, produces a natriuresis and a decrease in blood pressure that are short-lived (4, 5) and whose physiological role is still undefined (6, 7).The approach of essentially all other workers has been to investigate mammalian-derived isolates that inhibit the Na+ pump (2,8). From these studies, digoxin (9) and "iso-ouabain" (10-13) have been isolated; however, digoxin and ouabain lead to kaliuresis (4,(14)(15)(16)(17). Therefore, we hypothesized that this search tool is an inadequate marker for natriuresis. Consequently, a natriuretic assay has been developed in which the in vivo physiological events, urine volume, K+ and Na+ concentrations, and mean arterial pressure are measured (18).In this paper, we report the isolation of pure LLU-a, the determination of its structure by spectroscopy, its synthesis in racemic form, and its biological characterization. Given its structure, we infer that it is the product of in vivo oxidative metabolism of y-tocopherol, a member of the vitamin E complex. MATERIALS AND METHODSPurification of LLU-a. Human uremic urine (800 liters) was collected, processed by ultrafiltration (3 kDa) and lyophilization, and then chromatographed on Sephadex G-25 to obtain the post-salt fraction as described (18 Step 1. Reversed-phase HPLC was performed by gradient elution with 0.2 M pyridinium acetate, pH 5.5, and methanol as described (4). Based on bioassay data, fractions 50-80 were combined for further purification.Step 2. The next column (5 pm; 10 x 250 mm) was eluted at 2 ml/min with a gradient formed from...

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“…It is possible, therefore, that BTS 67 582 exerts it diuretic activity via inhibition of renal tubular KATP channels. The diuretics ZM181,037 [Kau et al, 1994] and U-37883A [Perricone et al, 1994;Humphrey et al, 1995;Humphrey, 1995] have been reported to cause eukalemic diuresis in dogs broadly similar to that observed with BTS 67 582. Interestingly, ZM181,037 and U-37883A [Wang et al, 1995] inhibit renal tubular KATP channel activity and possess functional antagonism of KATP channels in vascular tissue, but are devoid of glucose-lowering activity.…”

Section: Discussionmentioning

confidence: 82%