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Br J Pharmacol
2003 Aug 01;1397:1255-64. doi: 10.1038/sj.bjp.0705364.
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Structural requisites of 2-(p-chlorophenoxy)propionic acid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC-1.
Liantonio A
,
De Luca A
,
Pierno S
,
Didonna MP
,
Loiodice F
,
Fracchiolla G
,
Tortorella P
,
Antonio L
,
Bonerba E
,
Traverso S
,
Elia L
,
Picollo A
,
Pusch M
,
Camerino DC
.
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(1) The 2-(p-chlorophenoxy)propionic acid (CPP) modulates in a stereoselective manner the macroscopic chloride conductance (gCl), the electrical parameter sustained by the CLC-1 channel, of skeletal muscle. In order to determine the structural requirements for modulating native gCl and to identify high-affinity ligands, the effects of newly synthesised CPP analogues have been evaluated on gCl of rat EDL muscle fibres by means of the two-microelectrode current-clamp technique. (2) Each type of the following independent modification of CPP structure led to a three- to 10-fold decrease or to a complete lack of gCl-blocking activity: replacement of the electron-attractive chlorine atom of the aromatic ring, substitution of the oxygen atom of the phenoxy group, modification at the chiral centre and substitution of the carboxylic function with a phosphonate one. (3) The analogues bearing a second chlorophenoxy group on the asymmetric carbon atom showed a significant gCl-blocking activity. Similar to racemate CPP, the analogue with this group, spaced by an alkyl chain formed by three methylenic groups, blocked gCl by 45% at 100 micro M. (4) These latter derivatives were tested on heterelogously expressed CLC-1 performing inside-out patch-clamp recordings to further define how interaction between drug and channel protein could take place. Depending on the exact chemical nature of modification, these derivatives strongly blocked CLC-1 with K(D) values at -140 mV ranging from about 4 to 180 micro M. (5) In conclusion, we identified four molecular determinants pivotal for the interaction with the binding site on muscle CLC-1 channels: (a) the carboxylic group that confers the optimal acidity and the negative charge; (b) the chlorophenoxy moiety that might interact with a hydrophobic pocket; (c) the chiral centre that allows the proper spatial disposition of the molecule; (d) an additional phenoxy group that remarkably stabilises the binding by interacting with a second hydrophobic pocket.
Aromataris,
Modulation of the gating of CIC-1 by S-(-) 2-(4-chlorophenoxy) propionic acid.
1999, Pubmed
Aromataris,
Modulation of the gating of CIC-1 by S-(-) 2-(4-chlorophenoxy) propionic acid.
1999,
Pubmed
Bettoni,
Stereospecificity of the chloride ion channel: the action of chiral clofibric acid analogues.
1987,
Pubmed
Bryant,
Chloride channel regulation in the skeletal muscle of normal and myotonic goats.
1991,
Pubmed
Calleri,
Evaluation of a penicillin G acylase-based chiral stationary phase towards a series of 2-aryloxyalkanoic acids, isosteric analogs and 2-arylpropionic acids.
2002,
Pubmed
Carbonara,
Carboxylic acids and skeletal muscle chloride channel conductance: effects on the biological activity induced by the introduction of an aryloxyalkyl group alpha to the carboxylic function of 4-chloro-phenoxyacetic acid.
2001,
Pubmed
Chua,
Characterization of ion channels on the surface membrane of adult rat skeletal muscle.
1991,
Pubmed
Conte-Camerino,
Enantiomers of clofibric acid analogs have opposite actions on rat skeletal muscle chloride channels.
1988,
Pubmed
De Luca,
Opposite effects of enantiomers of clofibric acid derivative on rat skeletal muscle chloride conductance: antagonism studies and theoretical modeling of two different receptor site interactions.
1992,
Pubmed
De Luca,
Phosphorylation and IGF-1-mediated dephosphorylation pathways control the activity and the pharmacological properties of skeletal muscle chloride channels.
1998,
Pubmed
De Luca,
Aging and chloride channel regulation in rat fast-twitch muscle fibres.
1994,
Pubmed
De Luca,
Chloride channels of skeletal muscle from developing, adult and aged rats are differently affected by enantiomers of 2-(p-chlorophenoxy) propionic acid.
1992,
Pubmed
Dutzler,
X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity.
2002,
Pubmed
Ferorelli,
Isosteres of chiral clofibric acid analogs: synthesis, resolution, absolute configuration and HPLC detection of the optical purity.
1997,
Pubmed
Ferorelli,
Carboxylic acids and skeletal muscle chloride channel conductance: effects on the biological activity induced by the introduction of methyl groups on the aromatic ring of chiral alpha-(4-chloro-phenoxy)alkanoic acids.
2001,
Pubmed
Jentsch,
Molecular structure and physiological function of chloride channels.
2002,
Pubmed
Koch,
The skeletal muscle chloride channel in dominant and recessive human myotonia.
1992,
Pubmed
Liantonio,
Molecular requisites for drug binding to muscle CLC-1 and renal CLC-K channel revealed by the use of phenoxy-alkyl derivatives of 2-(p-chlorophenoxy)propionic acid.
2002,
Pubmed
,
Xenbase
Loiodice,
Carboxylic acids and chloride conductance in skeletal muscle: influence on the pharmacological activity induced by the chain substituents and the distance between the phenolic group and the carboxylic function in 4-chloro-phenoxy alkanoic acids.
1993,
Pubmed
Pusch,
Mechanism of block of single protopores of the Torpedo chloride channel ClC-0 by 2-(p-chlorophenoxy)butyric acid (CPB).
2001,
Pubmed
,
Xenbase
Pusch,
Pharmacological characterization of chloride channels belonging to the ClC family by the use of chiral clofibric acid derivatives.
2000,
Pubmed
,
Xenbase
Pusch,
Low single channel conductance of the major skeletal muscle chloride channel, ClC-1.
1994,
Pubmed
,
Xenbase
Pusch,
Mechanisms of block of muscle type CLC chloride channels (Review).
2002,
Pubmed
Romstedt,
Differential eudismic ratios in the antagonism of human platelet function by phenoxy- and thiophenoxyacetic acids.
1996,
Pubmed
Rosenbohm,
Regulation of the human skeletal muscle chloride channel hClC-1 by protein kinase C.
1999,
Pubmed
Steinmeyer,
Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel.
1991,
Pubmed
,
Xenbase
Witiak,
6-Chlorochroman-2-carboxylic acids. Synthesis and biological evaluation as antagonists for cholesterol biosynthesis and lipolysis in vitro.
1971,
Pubmed
Witiak,
Inhibitory action of -(4-chlorophenoxy)- -methylpropionic acid analogs on cholesterol biosynthesis and lipolysis in vitro.
1971,
Pubmed
