EFFECTS OF FENAMATES AND OTHER NONSTEROIDAL ANTIINFLAMMATORY DRUGS ONRAT-BRAIN GABA(A) RECEPTORS EXPRESSED IN XENOPUS-OOCYTES

Xenopus oocytes injected with poly(A)(+) RNA from rat cerebral cortex express functional gamma-aminobutyric acid (GABA)(A) receptors with el ectrical properties and pharmacology similar to those of receptors stu died in situ. Fenamates, a class of nonsteroidal anti-inflammatory dru gs (NSAIDs), had a dual effect on GABA-activated membrane current resp onses. Currents elicited by low concentrations of GABA were potentiate d, whereas currents elicited by high concentrations of GABA were inhib ited. The levels of the two effects varied among fenamates. For exampl e, 10 mu M mefenamic acid potentiated 10 mu M GABA responses by approx imately 300% (EC(50) approximate to 5 mu M) and inhibited maximal resp onses by 30% (IC50 approximate to 30 mu M). In contrast, 10 mu M niflu mic acid potentiated 10 mu M GABA responses by only 30% (EC(50) approx imate to 10 mu M) and inhibited maximal responses by 60% (IC50 approxi mate to 7 mu M). Preliminary structure-activity studies suggested that modulatory activity is dependent on the preferred conformations of fe namate molecules and on specific phenyl-ring substitutions. Thirteen o ther NSAIDs (all prostaglandin synthesis inhibitors) were likewise ass ayed for effects on GABA-activated currents. Of these, only the salicy lic acid diflunisal induced comparable potentiation and inhibition. Ou r experiments raise two interesting possibilities: that fenamates coul d serve as lead structures in the development of novel GABA(A) recepto r modulators and that fenamates might affect GABA(A) receptor function at a normal clinical dosage.