Halide and alkyl phenols block volume-sensitive chloride channels in human glial cells (U-138MG)

Swelling of cells in hypotonic media activates a volume-sensitive Cl channel with well-known characteristics, but its structure and its regulation are still largely undetermined. It also has many inhibitors and most of them are also blocking other types of Cl channels. The numerous inhibitors of Cl channels have apparently no structural relationship among them. The purpose of this study was to try to determine the most simple molecules that could block these channels and identify some common properties among inhibitors. From the 37 new molecules that were studied, it was found that simple halide phenols like trichloro and triiodophenols could block these channels in the micromolar range. Also alkyl phenols, like butylphenols, are very sensitive blockers, comparable to other well-known blockers. But acidic halide phenols or nitrophenols are poor blockers. Also neutral polyphenols are more sensitive than acidic polyphenols. All these results indicate that the common basis for blocking these Cl channels is a phenol with hydrophobic groups, like short alkyl chains or an additional phenyl ring, attached to some of its sites, preferably sites 3-4-5. These results identify a new family of Cl channel blockers and hopefully improve our understanding of the blocking mechanism.