Arylaminobenzoate Block of the Cardiac Cyclic AMP-Dependent Chloride Current

Walsh, Kenneth B.; Wang, Chongmin

doi:10.1124/mol.53.3.539

Cited by 21 publications

(20 citation statements)

References 39 publications

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“…These characteristics can be observed in a broad range of compounds that inhibit CFTR. These include the sulfonylureas [16], arylaminobenzoates [18,19], disulfonic stilbenes [20], conjugated steroids and bile acids [21], shortchain fatty acids [22], and organic anions [23]. All these CFTR-channel blockers act preferentially from the intracellular side, perhaps due to their abilities to bind within a large, cytoplasmically accessible vestibule of the channel pore [24].…”

Section: Discussionmentioning

confidence: 98%

Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels in Rat Epididymal Epithelial Cells1

Gong

Linsdell

Cheung

et al. 2002

Biology of Reproduction

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Previous studies have shown that two indazole compounds, lonidamine [1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid] and its analogue AF2785 [(1-(2,4-dichlorobenzyl)-indazol-3-acrylic acid], suppress fertility in male rats. We also found that these compounds inhibit the cystic fibrosis transmembrane conductance regulator chloride (CFTR-Cl(-)) current in epididymal epithelial cells. To further investigate how lonidamine and AF2785 inhibit the current, we used a spectral analysis protocol to study whole-cell CFTR current variance. Application of lonidamine or AF2785 to the extracellular membrane of rat epididymal epithelial cells introduced a new component to the whole-cell current variance. Spectral analysis of this variance suggested a block at a rate of 3.68 micro mol(-1)/sec(-1) and an off rate of 69.01 sec(-1) for lonidamine, and an on rate of 3.27 micro mol(-1)/sec(-1) and an off rate of 108 sec(-1) for AF2785. Single CFTR-Cl(-) channel activity using excised inside-out membrane patches from rat epididymal epithelial cells revealed that addition of lonidamine to the intracellular solution caused a flickery block (a reduction in channel-open time) at lower concentration (10 micro M) without any effect on open channel probability or single-channel current amplitude. At higher concentrations (50 and 100 micro M), lonidamine showed a flickery block and a decrease in open-channel probability. The flickery block by lonidamine was both voltage-dependent and concentration-dependent. These results suggest that lonidamine and AF2785, which are open-channel blockers of CFTR at low concentrations, also affect CFTR gating at high concentrations. We conclude that these indazole compounds provide new pharmacological tools for the investigation of CFTR. By virtue of their interference with reproductive processes, these drugs have the potential for being developed into novel male contraceptives.

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Section: Discussionmentioning

confidence: 98%

Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels in Rat Epididymal Epithelial Cells1

Gong

Linsdell

Cheung

et al. 2002

Biology of Reproduction

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“…In the case of chloride channels, arylaminobenzoates access the binding site in the uncharged form but bind to their receptor in the charged form after protonation in the cytoplasmic milieu (McCarty et al, 1993;McDonough et al, 1994;Walsh and Wang, 1998). Evidence that the charged form binds to the receptor and causes open-channel blockade was provided in those studies by 1) potent blockade by drug applied via patch pipettes, 2) voltage-dependence of block, 3) reduction of magnitude of blockade by substitution of chloride by a larger permeant ion, and 4) rapid flicker in the single-channel records in the presence of the drug.…”

Section: Resultsmentioning

confidence: 99%

“…More importantly, o-aminobenzoic acid and 2-amino-4-phenylbutyric acid caused little effect on Cx50 channels, strongly indicating that both the phenyl side chain and the benzoate ring are important for the inhibition of gap junction channel currents. To determine how externally applied FFA accesses its binding site, strategies that have been used to investigate the site of block by this drug in chloride channels were applied (Walsh and Wang, 1998;Zhang et al, 2000). Most arylaminobenzoates, including FFA, are weak acids with pK a values in range of 3 to 5 and therefore can exist in both the membrane-permeable uncharged form and the anionic-charged form, depending on the pH of the external solution.…”

Section: Resultsmentioning

confidence: 99%

“…Structure-activity studies of chloride-channel blockers defined four elements critical for arylaminobenzoate blockade: 1) the anionic carboxylate group, 2) the negative partial charge in meta (or para) position to the carboxylate group, 3) the amino "bridge" carrying a positive partial charge, and 4) the bulky hydrophobic side chain (Walsh and Wang, 1998;Walsh et al, 1999). Compounds that lacked the benzoate ring and/or those that decreased the acidity of this ring caused a marked attenuation in the potency.…”

Section: Discussionmentioning

confidence: 99%

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Closure of Gap Junction Channels by Arylaminobenzoates

Srinivas

Spray

2003

Mol Pharmacol

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We determined the effect of flufenamic acid (FFA) and related derivatives on gap junction channel currents, applying the dual whole-cell patch-clamp technique to pairs of N2A neuroblastoma cells transfected with various connexins. FFA reduced gap junction channel currents in a reversible and concentration-dependent manner. Half-maximal concentrations for FFAinduced reduction of junctional conductance in cell pairs coupled by different connexins were similar (20 to 60 M), indicating that FFA does not greatly discriminate between connexin subtypes. Hill coefficients for blockade were approximately 3, indicating a high degree of cooperativity. Analogs of FFA also reduced junctional conductance with similar potencies, whereas other unrelated chloride channel blockers had no effect. Inhibition of gap junction channels by FFA (pK a ϳ 3.8) was increased at low external pH, suggesting that the uncharged form of the drug is important for blockade. The effect of FFA did not seem to be mediated by direct binding of the drug to the pore of the gap junction channel. Internal application of high concentrations of FFA by addition to patch pipettes did not cause inhibition of channel currents. The magnitude of inhibition was neither voltage-dependent nor influenced by the nature of permeant ion. Single-channel recordings indicated that FFA reduced the channel-open probability without modifying the current amplitude and induced slow transitions between open and closed states. We propose that FFA inhibits gap junctions by inducing a conformational change in the protein upon binding to a site that is presumably located within the membrane.

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“…However, special attention should be paid to arylaminobenzoate compounds examined by Walsh and Wang [36]. They gave a characteristics of the following compounds: Interestingly, BNBA contains one carbon atom between the benzoate and phenyl rings, NPEB-two, NPPB-three and NPBA four carbon atoms.…”

Section: Selective Blockers Of I Clpkamentioning

confidence: 99%

Modulators of Ion Channels Activated by Hypotonic Swelling in Cardiomyocytes: New Perspectives for Pharmacological Treatment of Life-Threatening Arrhythmias

Kocić

2005

CMCCHA

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This review highlights the most important research data related to membrane potential and current changes in cardiomyocytes during hypotonic stress. Relative decrease in osmolarity in extracellular compartment (due to accumulation of metabolic products in the cells) during acute episodes of ischemia in the heart muscle leads to cell swelling caused by water entering the cells. Such condition starts regulatory volume decrease (RDV) in cardiomyocytes--a process involving activation of various ion channels. It seems to be the crucial proarrhythmic mechanism in ischemic heart, probably very often responsible for sudden cardiac death. Understanding of electrophysiological changes during hypotonic stress of cardiomyocytes is a basis for appropriate pharmacological intervention preventing serious arrhythmias. For instance, outwardly rectifying swelling-induced chloride currents (IClswell), inwardly rectifying non-selective cation current (INSC) and slow component of delayed rectifier K+ currents (IKs) are activated during hypotonic stress in ventricular myocytes and substances like anthracene-9-carboxylic acid (9-AC), chromanol (293B) and gadolinium (Gd3+), able to modulate former channels, should be considered to be potential antiarrhythmic drugs in the near future.

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Arylaminobenzoate Block of the Cardiac Cyclic AMP-Dependent Chloride Current

Cited by 21 publications

References 39 publications

Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels in Rat Epididymal Epithelial Cells1

Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels in Rat Epididymal Epithelial Cells1

Closure of Gap Junction Channels by Arylaminobenzoates

Modulators of Ion Channels Activated by Hypotonic Swelling in Cardiomyocytes: New Perspectives for Pharmacological Treatment of Life-Threatening Arrhythmias

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