Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Structure-activity relationships of bumetanide derivatives: correlation between diuretic activity in dogs and inhibition of the human NKCC2A transporter.
Lykke K
,
Töllner K
,
Römermann K
,
Feit PW
,
Erker T
,
MacAulay N
,
Löscher W
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na+ , K+ and Cl- ions across cell membranes. There are two isoforms of this cation co-transporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available.
EXPERIMENTAL APPROACH: In this study, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes.
KEY RESULTS: Bumetanide blocked hNKCC2A transport with an IC50 of 4 μM. There was good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A (r2 = 0.817; P < 0.01). Replacement of the carboxylic group of bumetanide by a non-ionic residue, for example, an anilinomethyl group, decreased inhibition of hNKCC2A, indicating that an acidic group was required for transporter inhibition. Exchange of the phenoxy group of bumetanide for a 4-chloroanilino group or the sulfamoyl group by a methylsulfonyl group resulted in compounds with higher potency to inhibit hNKCC2A than bumetanide.
CONCLUSIONS AND IMPLICATIONS: The X. laevis oocyte expression system used in these experiments allowed analysis of the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics.
Alexander,
The Concise Guide to PHARMACOLOGY 2013/14: transporters.
2013, Pubmed
Alexander,
The Concise Guide to PHARMACOLOGY 2013/14: transporters.
2013,
Pubmed
Ben-Ari,
Blocking seizures with the diuretic bumetanide: promises and pitfalls.
2012,
Pubmed
Burckhardt,
Drug transport by Organic Anion Transporters (OATs).
2012,
Pubmed
Carota,
Localization and functional characterization of the human NKCC2 isoforms.
2010,
Pubmed
,
Xenbase
Castrop,
Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance.
2008,
Pubmed
Cohen,
A comparative diuretic and tissue distribution study of bumetanide and furosemide in the dog.
1976,
Pubmed
Cohen,
Pharmacology of bumetanide.
1981,
Pubmed
Delpire,
Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter.
1999,
Pubmed
Delpire,
Molecular cloning and chromosome localization of a putative basolateral Na(+)-K(+)-2Cl- cotransporter from mouse inner medullary collecting duct (mIMCD-3) cells.
1994,
Pubmed
Feit,
Aminobenzioc acid diuretics. 8.(2) 3, 4-Disubstituted 5-methylsulfonylbenzioc acids and related compounds.
1976,
Pubmed
Feit,
Bumetanide--the way to its chemical structure.
1981,
Pubmed
Feit,
Aminobenzoic acid diuretics. 1. 4-Halogeno-5-sulfamylmetanilic acid derivatives.
1970,
Pubmed
Feit,
Aminobenzoic acid diuretics. 6. 4-Substituted 3-alkylthio-5-sulfamoylbenzoic and 5-sulfamoylthiosalicylic acids.
1974,
Pubmed
Feit,
Aminobenzoic acid diuretics. 2. 4-Substituted-3-amino-5-sulfamylbenzoic acid derivatives.
1971,
Pubmed
Fenton,
Differential water permeability and regulation of three aquaporin 4 isoforms.
2010,
Pubmed
,
Xenbase
Flatman,
Regulation of Na+-K+-2Cl- cotransport by protein phosphorylation in ferret erythrocytes.
1999,
Pubmed
Frey,
Pharmacology of bumetanide.
1975,
Pubmed
Frizzell,
Sodium-coupled chloride transport by epithelial tissues.
1979,
Pubmed
Gamba,
Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney.
1994,
Pubmed
,
Xenbase
Garay,
What can we learn from erythrocyte Na-K-Cl cotransporter NKCC1 in human hypertension?
2007,
Pubmed
Haas,
The Na-K-Cl cotransporters.
1998,
Pubmed
Hannaert,
Rat NKCC2/NKCC1 cotransporter selectivity for loop diuretic drugs.
2002,
Pubmed
Kahle,
Roles of the cation-chloride cotransporters in neurological disease.
2008,
Pubmed
Kahle,
The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures.
2008,
Pubmed
Kaila,
Cation-chloride cotransporters in neuronal development, plasticity and disease.
2014,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Löscher,
Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments.
2013,
Pubmed
Markadieu,
Physiology and pathophysiology of SLC12A1/2 transporters.
2014,
Pubmed
Matskevich,
Regulation of erythrocyte Na-K-2Cl cotransport by threonine phosphorylation.
2005,
Pubmed
McGrath,
Guidelines for reporting experiments involving animals: the ARRIVE guidelines.
2010,
Pubmed
Mälkiä,
Drug permeation in biomembranes: in vitro and in silico prediction and influence of physicochemical properties.
2004,
Pubmed
Noebels,
Chloride homeostasis and GABA signaling in temporal lobe epilepsy
2012,
Pubmed
Olsen,
The pharmacology of bumetanide.
1977,
Pubmed
Orita,
A metal complexing property of furosemide and bumetanide: determination of pK and stability constant.
1976,
Pubmed
Ostergaard,
Pharmacological properties of 3-n-butylamino-4-phenoxy-5-sulfamylbenzoic acid (Bumetanide), a new potent diuretic.
1972,
Pubmed
Palfrey,
cAMP-stimulated cation cotransport in avian erythrocytes: inhibition by "loop" diuretics.
1980,
Pubmed
Pawson,
The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands.
2014,
Pubmed
Petzinger,
What we have learned about bumetanide and the concept of multispecific bile acid/drug transporters from the liver.
1996,
Pubmed
Petzinger,
Interaction of bumetanide derivatives with hepatocellular bile acid uptake.
1993,
Pubmed
Plata,
Functional properties of the apical Na+-K+-2Cl- cotransporter isoforms.
2002,
Pubmed
,
Xenbase
Pressler,
Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.
2015,
Pubmed
Pressler,
Newly emerging therapies for neonatal seizures.
2013,
Pubmed
Puskarjov,
Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures.
2014,
Pubmed
Rybak,
Ototoxicity of loop diuretics.
1993,
Pubmed
Rybak,
Ototoxicity.
2007,
Pubmed
Shneider,
Characterization of endogenous carrier-mediated taurocholate efflux from Xenopus laevis oocytes.
1993,
Pubmed
,
Xenbase
Sobczak,
Endogenous transport systems in the Xenopus laevis oocyte plasma membrane.
2010,
Pubmed
,
Xenbase
Somasekharan,
Loop diuretic and ion-binding residues revealed by scanning mutagenesis of transmembrane helix 3 (TM3) of Na-K-Cl cotransporter (NKCC1).
2012,
Pubmed
Suvitayavat,
Characterization of the endogenous Na(+)-K(+)-2Cl- cotransporter in Xenopus oocytes.
1994,
Pubmed
,
Xenbase
Töllner,
A novel prodrug-based strategy to increase effects of bumetanide in epilepsy.
2014,
Pubmed
Töpfer,
Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy.
2014,
Pubmed
VanWert,
Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology.
2010,
Pubmed
Ward,
Bumetanide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use.
1984,
Pubmed
Xu,
Molecular cloning and functional expression of the bumetanide-sensitive Na-K-Cl cotransporter.
1994,
Pubmed
Zeuthen,
Cotransport of water by Na⁺-K⁺-2Cl⁻ cotransporters expressed in Xenopus oocytes: NKCC1 versus NKCC2.
2012,
Pubmed
,
Xenbase