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kg) 1 h before cysteamine treatment reduced duodenal
ulceration (Akiba et al., 2005). Finally, CFTR inhibitors,
such as CFTRinh-172, glibenclamide, and 5-nitro-2-(3-phe-
nylpropylamino)-benzoic acid, by inhibiting transepithe-
lial ion transport, retard renal cyst growth using MDCK
cells as a model (Li et al., 2004), suggesting that such
molecules could contribute to the pharmacological treat-
ment of autosomal-dominant polycystic kidney disease.
Advantage of ␣-Aminoazaheterocycle-Methylglyoxal
Adducts to Inhibit CFTR. In our first report on reaction of
methylglyoxal with ␣-aminoazaheterocycle leading to a new
class of compounds, X-ray studies of crystals 2a, 2b, and 4a
revealed the zwitterionic character of the products
(Routaboul et al., 2002). The presence of an amino acid-like
function confers to the products interesting water solubility.
The water solubility of compound 5a is higher than 55 mM,
and the less soluble inhibitors in water are compounds 8a,b,
showing a maximum solubility around 8 mM. The resulting
zwitterionic character of the inhibitors in water under neu-
tral conditions also could be a major element in the mecha-
nism of the inhibitory effect. The opposite charges present in
the inhibitors could lead to their strong binding to charged
amino acid residues in the CFTR protein and produce a major
switch in the protein conformation controlling the ClϪ chan-
nel activity. Although the mechanism of inhibition of CFTR
by adducts 5a and 8a,b has not yet been studied, these
compounds already have some advantages over existing in-
hibitors. First, these agents are water-soluble and nontoxic;
second, they are effective at extremely low concentrations;
third, the inhibition in the whole-cell patch-clamp experi-
ments of CFTR activity is very rapid, reversible, and repro-
ducible, and fourth, these agents are able to inhibit cAMP-
dependent chloride secretion in an intact tissue, the mouse
colon, at picomolar concentrations. To our knowledge pico-
molar efficacy is not common in the pharmacology area of
ionic channels for a small molecule, except for some channel-
specific toxins (Mouhat et al., 2004; Terlau and Olivera,
2004). Therefore, ␣-aminoazaheterocycle-methylglyoxal ad-
ducts could be useful tools for studying CFTR structure and
functions and epithelial pharmacology. Future development
of these compounds may potentially provide new therapeutic
antidiarrheal, anticholeric, antiulceration, and anti-autoso-
mal-dominant polycystic kidney disease agents.
Acknowledgments
Perez A, Issler AC, Cotton CU, Kelley TJ, Verkman AS, and Davis PB (2007) CFTR
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Mol Physiol 292:L383–L395.
We thank Nathalie Bizard for excellent technical assistance.
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