Modifications of diflunisal and meclofenamate carboxyl groups affect their allosteric effects on GABAA receptor ligand binding.

Gamma-aminobutyric acid type A receptors (GABAAR) are allosterically modulated by the nonsteroidal anti-inflammatory drugs diflunisal and fenamates. The carboxyl group of these compounds is charged at physiological pH and therefore penetration of the compounds into the brain is low. In the present study we have transformed the carboxyl group of diflunisal and meclofenamate into non-ionizable functional groups and analyzed the effects of the modifications on stimulation of [(3)H]muscimol binding and on potentiation of γ-aminobutyric acid-induced displacement of 4'-ethenyl-4-n-[2,3-(3)H]propylbicycloorthobenzoate. N-Butylamide derivative of diflunisal modulated radioligand binding with equal or higher potency than the parent compound, while diflunisalamide showed reduced allosteric effect as compared to diflunisal. Amide derivative of meclofenamate equally affected radioligand binding parameters, while both diflunisal and meclofenamate methyl esters were less active than the parent compounds. Our study clearly demonstrates that an intact carboxyl group in diflunisal and meclofenamate is not indispensable for their positive GABAAR modulation. Further derivatization of the compound might yield compounds with higher selectivity for GABAARs that could be utilized in drug development.