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American Journal of Physiology. Renal... Oct 2023The primary structure of the thiazide-sensitive NaCl cotransporter (NCC) was resolved 30 years ago by the molecular identification of the cDNA encoding this... (Review)
Review
The primary structure of the thiazide-sensitive NaCl cotransporter (NCC) was resolved 30 years ago by the molecular identification of the cDNA encoding this cotransporter, from the winter's flounder urinary bladder, following a functional expression strategy. This review outlines some aspects of how the knowledge about thiazide diuretics and NCC evolved, the history of the cloning process, and the expansion of the SLC12 family of electroneutral cotransporters. The diseases associated with activation or inactivation of NCC are discussed, as well as the molecular model by which the activity of NCC is regulated. The controversies in the field are discussed as well as recent publication of the three-dimensional model of NCC obtained by cryo-electron microscopy, revealing not only the amino acid residues critical for Na and Cl translocation but also the residues critical for polythiazide binding to the transporter, opening the possibility for a new era in thiazide diuretic therapy.
Topics: Solute Carrier Family 12, Member 3; Protein Serine-Threonine Kinases; Sodium Chloride; Cryoelectron Microscopy; Sodium Chloride Symporter Inhibitors; Cloning, Molecular
PubMed: 37560773
DOI: 10.1152/ajprenal.00114.2023 -
The AAPS Journal Apr 2013Target identification of the known bioactive compounds and novel synthetic analogs is a very important research field in medicinal chemistry, biochemistry, and... (Comparative Study)
Comparative Study
Target identification of the known bioactive compounds and novel synthetic analogs is a very important research field in medicinal chemistry, biochemistry, and pharmacology. It is also a challenging and costly step towards chemical biology and phenotypic screening. In silico identification of potential biological targets for chemical compounds offers an alternative avenue for the exploration of ligand-target interactions and biochemical mechanisms, as well as for investigation of drug repurposing. Computational target fishing mines biologically annotated chemical databases and then maps compound structures into chemogenomical space in order to predict the biological targets. We summarize the recent advances and applications in computational target fishing, such as chemical similarity searching, data mining/machine learning, panel docking, and the bioactivity spectral analysis for target identification. We then described in detail a new web-based target prediction tool, TargetHunter (http://www.cbligand.org/TargetHunter). This web portal implements a novel in silico target prediction algorithm, the Targets Associated with its MOst SImilar Counterparts, by exploring the largest chemogenomical databases, ChEMBL. Prediction accuracy reached 91.1% from the top 3 guesses on a subset of high-potency compounds from the ChEMBL database, which outperformed a published algorithm, multiple-category models. TargetHunter also features an embedded geography tool, BioassayGeoMap, developed to allow the user easily to search for potential collaborators that can experimentally validate the predicted biological target(s) or off target(s). TargetHunter therefore provides a promising alternative to bridge the knowledge gap between biology and chemistry, and significantly boost the productivity of chemogenomics researchers for in silico drug design and discovery.
Topics: Algorithms; Anti-HIV Agents; Antihypertensive Agents; Antineoplastic Agents; Artificial Intelligence; Benzofurans; Computer Graphics; Computer Simulation; Data Mining; Databases, Chemical; Drug Discovery; Drug Repositioning; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Muscarinic Antagonists; Polythiazide; Pyrrolidines; Reproducibility of Results; Software; Structure-Activity Relationship; User-Computer Interface
PubMed: 23292636
DOI: 10.1208/s12248-012-9449-z -
Acta Crystallographica. Section E,... Jun 2010The crystal structure of the title compound, C(11)H(13)ClF(3)N(3)O(4)S(3) (systematic name:...
The crystal structure of the title compound, C(11)H(13)ClF(3)N(3)O(4)S(3) (systematic name: 6-chloro-2-methyl-3-{[(2,2,2-trifluoro-eth-yl)sulfan-yl]meth-yl}-3,4-dihydro-2H-1,2,4-benzothia-diazine-7-sul-f-on-amide 1,1-diox-ide; CRN: 346-18-9), exhibits a two-dimensional network of hydrogen-bonded mol-ecules parallel to (01). The NH and NH(2) groups act as donor sites and the sulfonyl O atoms as acceptor sites in N-H⋯O hydrogen bonds, and a C-H⋯O interaction also occurs. The thiadiazine ring adopts an envelope conformation with the N atom bonded to sulfur at the tip of the flap, and the methyl substituent is in an axial position.
PubMed: 21587890
DOI: 10.1107/S1600536810022105 -
Therapeutic Drug Monitoring Aug 2005A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of diuretics, uricosurics, and/or their metabolites in human...
Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation.
A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of diuretics, uricosurics, and/or their metabolites in human urine after extractive methylation. Phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by GC and identified by MS in the full-scan mode. The possible presence of the following drugs and/or their metabolites could be indicated using mass chromatography with the given ions: m/z 267, 352, 353, 355, 386, and 392 for thiazide diuretics bemetizide, bendroflumethiazide, butizide, chlorothiazide, cyclopenthiazide, cyclothiazide, hydrochlorothiazide, metolazone, polythiazide, and for canrenoic acid and spironolactone; m/z 77, 81, 181, 261, 270, 295, 406, and 438 for loop diuretics bumetanide, ethacrynic acid, furosemide, piretanide, torasemide, as well as the uricosurics benzbromarone, probenecid, and sulfinpyrazone; m/z 84, 85, 111, 112, 135, 161, 249, 253, 289, and 363 for the other diuretics acetazolamide, carzenide, chlorthalidone, clopamide, diclofenamide, etozoline, indapamide, mefruside, tienilic acid, and xipamide. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with reference spectra. This method allowed the detection of the abovementioned drugs and/or their metabolites in human urine samples, except torasemide. The limits of detection ranged from 0.001 to 5 mg/L in the full-scan mode. Recoveries of selected diuretics and uricosurics, representing the different chemical classes, ranged from 46% to 99% with coefficients of variation of less than 21%. After ingestion of the lowest therapeutic doses, furosemide was detectable in urine samples for 67 hours, hydrochlorothiazide for 48 hours, and spironolactone for 52 hours (via its target analyte canrenone). The procedure described here is part of a systematic toxicological analysis procedure for acidic drugs and poisons.
Topics: Diuretics; Drug Monitoring; Gas Chromatography-Mass Spectrometry; Humans; Methylation; Reproducibility of Results; Uricosuric Agents; Urinalysis
PubMed: 16044110
DOI: 10.1097/01.ftd.0000160719.96445.91 -
Wiener Klinische Wochenschrift 2001Approximately 30 patients with familial hypomagnesemia-hypercalciuria have been reported. We describe an 8-year-old girl with cardinal findings of familial...
Approximately 30 patients with familial hypomagnesemia-hypercalciuria have been reported. We describe an 8-year-old girl with cardinal findings of familial hypomagnesemia-hypercalciuria (hypomagnesemia, hypermagnesiuria, hypercalciuria, renal insufficiency, hyperuricemia, elevated serum parathormone, hyposthenuria and nephrocalcinosis), who received combination therapy consisting of magnesium salts, thiazide diuretic and potassium supplementation. At the 4-year follow-up investigation under this treatment, the patient was found to have cerebral pseudotumor (increased intracranial pressure with normal or small ventricles on neuroimaging, no evidence of an intracranial mass and normal cerebrospinal fluid composition) with papilledema and visual field defects. Thiazide therapy was terminated and the cerebral pseudotumor disappeared. The authors hypothesize that cerebral pseudotumor in this patient was related to severe hypocalcemia, as a consequence of profound hypomagnesemia induced by protracted thiazide treatment. To our knowledge, this is the first report of a child with familial hypomagnesemia-hypercalciuria who developed pseudotumor cerebri after thiazide therapy.
Topics: Calcium; Child; Diuretics; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypocalcemia; Magnesium Compounds; Magnesium Deficiency; Nephrocalcinosis; Polythiazide; Potassium; Pseudotumor Cerebri; Risk Factors; Sodium Chloride Symporter Inhibitors
PubMed: 15503623
DOI: No ID Found -
American Journal of Physiology. Renal... Oct 2002To test the role of epithelial Na channels in the day-to-day regulation of renal Na excretion, rats were infused via osmotic minipumps with the Na channel blocker...
To test the role of epithelial Na channels in the day-to-day regulation of renal Na excretion, rats were infused via osmotic minipumps with the Na channel blocker amiloride at rates that achieved drug concentrations of 2-5 microM in the lumen of the distal nephron. Daily Na excretion rates were unchanged, although amiloride-treated animals tended to excrete more Na in the afternoon and less in the late evening than controls. When the rats were given a low-Na diet, Na excretion rates were elevated in the amiloride-treated group within 4 h and remained higher than controls for at least 48 h. Adrenalectomized animals responded similarly to the low-Na diet. In contrast, rats infused with polythiazide at rates designed to inhibit NaCl transport in the distal tubule were able to conserve Na as well as did the controls. Injection of aldosterone (2 microg/100 g body wt) decreased Na excretion in control animals after a 1-h delay. This effect was largely abolished in amiloride-treated rats. On the basis of quantitative analysis of the results, we conclude that activation of amiloride-sensitive channels by mineralocorticoids accounts for 50-80% of the immediate natriuretic response of the kidney to a reduction in Na intake. Furthermore, the channels are necessary to achieve minimal rates of Na excretion during more chronic Na deprivation.
Topics: Aldosterone; Amiloride; Animals; Chromatography, High Pressure Liquid; Circadian Rhythm; Diet, Sodium-Restricted; Diuretics; Electrolytes; Epithelial Cells; Female; Kidney; Kidney Tubules, Collecting; Kinetics; Polythiazide; Rats; Rats, Sprague-Dawley; Sodium; Sodium Channel Blockers; Sodium Channels; Sodium Chloride Symporter Inhibitors
PubMed: 12217863
DOI: 10.1152/ajprenal.00379.2001 -
American Journal of Physiology. Renal... Jul 2000The thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) is the major pathway for salt reabsorption in the apical membrane of the mammalian distal convoluted tubule. When...
The thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) is the major pathway for salt reabsorption in the apical membrane of the mammalian distal convoluted tubule. When expressed in Xenopus laevis oocytes, rat TSC exhibits high affinity for both cotransported ions, with the Michaelis-Menten constant (K(m)) for Na(+) of 7.6 +/- 1.6 mM and for Cl(-) of 6.3 +/- 1.1 mM, and Hill coefficients for Na(+) and Cl(-) consistent with electroneutrality. The affinities of both Na(+) and Cl(-) were increased by increasing concentration of the counterion. The IC(50) values for thiazides were affected by both extracellular Na(+) and Cl(-). The higher the Na(+) or Cl(-) concentration, the lower the inhibitory effect of thiazides. Finally, rTSC function is affected by extracellular osmolarity. We propose a transport model featuring a random order of binding in which the binding of each ion facilitates the binding of the counterion. Both ion binding sites alter thiazide-mediated inhibition of transport, indicating that the thiazide-binding site is either shared or modified by both Na(+) and Cl(-).
Topics: Animals; Bendroflumethiazide; Binding Sites; Biological Transport; Carrier Proteins; Chlorides; Diuretics; Hydrochlorothiazide; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Kinetics; Metolazone; Microinjections; Models, Biological; Oocytes; Osmolar Concentration; Polythiazide; Rats; Receptors, Drug; Sodium; Sodium Chloride Symporter Inhibitors; Sodium Chloride Symporters; Solute Carrier Family 12, Member 3; Symporters; Xenopus
PubMed: 10894798
DOI: 10.1152/ajprenal.2000.279.1.F161 -
Archives Des Maladies Du Coeur Et Des... Aug 1999Although the renal receptor at which cicletanine acts is unknown, cicletanine was assumed to act like thiazide diuretics. Here we tested cicletanine and its natriuretic...
UNLABELLED
Although the renal receptor at which cicletanine acts is unknown, cicletanine was assumed to act like thiazide diuretics. Here we tested cicletanine and its natriuretic metabolite, cicletanine-sulfate, for inhibitory activity against the thiazide-sensitive NaCl cotransporter expressed in Xenopus oocytes. The renal thiazide-sensitive NaCl cotransporter was expressed in Xenopus laevis oocytes injected with rat cRNA TSCr (TSCr: thiazide-sensitive cotransporter from rat kidney) and both, racemic (+/-) cicletanine and its sulfoconjugated metabolite were tested for inhibitory activity against oocyte 22Na+ uptake catalyzed by this cotransporter. Polythiazide was used as reference thiazide. Polythiazide fully inhibited NaCl cotransporter function with IC50 approximately 1.2 x 10(-7) M. Conversely, neither cicletanine, nor cicletanine sulfate were able to inhibit such cotransporter, i.e.: a minimum concentration of 10(-4) M of cicletanine was necessary to induce a slight cotransporter inhibition (29.5 +/- 18.2%). Cicletanine sulfate was inactive, even at 10(-4) M.
IN CONCLUSION
(i) the natriuretic metabolite of cicletanine (cicletanine sulfate) is unable to inhibit thiazide-sensitive NaCl cotransporter and (ii) inhibition of such cotransporter by cicletanine required concentrations equal or higher than 10(-4) M--concentrations much more higher than urinary therapeutic ones in humans (approximately 10(-6) M). These results clearly demonstrate that cicletanine does not act like thiazide diuretics.
Topics: Animals; Benzothiadiazines; Carrier Proteins; Diuretics; Female; Oocytes; Pyridines; Receptors, Drug; Sodium Chloride Symporter Inhibitors; Sodium Chloride Symporters; Sodium Radioisotopes; Symporters; Xenopus laevis
PubMed: 10486654
DOI: No ID Found