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Vol. 58, Issue 3, 498-507, September 2000
Istituto di Cibernetica e Biofisica, CNR, Genova (M.P., A.L., L.B.,
A.A.); and Unità di Farmacologia, Dipartimento Farmacobiologico
(A.D.L., S.P., D.C.C.) and Dipartimento Farmacochimico (V.T.),
Università di Bari, Bari, Italy
The enantiomers of 2-(p-chlorophenoxy)propionic acid
(CPP) and of its analogs with substitutions on the asymmetric carbon atom were tested on human ClC-1 channel, the skeletal muscle chloride channel, after heterologous expression in Xenopus laevis
oocytes, to gain insight in the mechanism of action of these
stereoselective modulators of macroscopic chloride conductance (gCl) of
rat striated fibers. By means of two microelectrode voltage clamp
recordings, we found that S(
)-CPP shifted the
activation curve of the ClC-1 currents toward more positive potentials
and decreased the residual conductance at negative membrane potential;
both effects probably account for the decrease of gCl at resting
potential of native muscle fibers. Experiments on expressed
Torpedo marmorata ClC-0 channels and a mutant
lacking the slow gate suggest that S()-CPP could act
on the fast gate of the single protochannels constituting the
double-barreled structure of ClC-0 and ClC-1. The effect of S()-CPP on ClC-1 was markedly increased at low
external pH (pH = 6), possibly for enhanced diffusion through the
membrane (i.e., because the compound was effective only when applied to
the cytoplasmic side during patch clamp recordings). The
R(+)-isomer had little effect at concentrations as high
as 1 mM. The CPP analogs with an ethyl, a phenyl, or an
n-propyl group in place of the methyl group on the
asymmetric center showed a scale of potency and a stereoselective
behavior on ClC-1 similar to that observed for blocking gCl in native
muscle fibers. The tested compounds were selective toward the ClC-1
channel. In fact, they were almost ineffective on an N-terminal
deletion mutant of ClC-2 that is volume- and pH-independent
while they blocked wild-type ClC-2 currents only at high
concentrations and independently of pH and drug configuration,
suggesting a different mechanism of action compared with ClC-1. No
effects were observed on ClC-5 that shows less than 30%
homology with ClC-1. Thus, CPP-like compounds may be useful both to
gain insight into biophysical properties of ClC-1 and for searching
tissue-specific therapeutic agents.
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