INHIBITION OF BRAIN GLUTAMATE DECARBOXYLASE BY 4, 5-DIHYDROXYISOPHTHALIC ACID AND RELATED COMPOUNDS

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Hydroxybenzoic and phthalic acids and their related compounds were tested for inhibitory activity to brain glutamate decarboxylase. Of mono-, di-, and trihydroxybenzoic acids, gallic acid was the most inhibitory, giving 50% inhibition at a concentration of 0.17 mm. Dihydroxybenzoic acids were less inhibitory than the trihydroxyacids but more than monohydroxybenzoic acids. Of the phthalic acid-related compounds tested, 4, 5-dihydroxyisophthalic acid was the most potent inhibitor, producing 50% inhibition at 0.61 μm. The inhibition of these compounds was competitive with respect to L-glutamate. The Ki values were 0.02, 1.2 and 4.9 pM for 4, 5-dihydroxyisophthalic acid, 5-hydroxyisophthalic acid and gallic acid, respectively. When administered intraventricularly to mice, 4, 5-dihydroxyisophthalic acid produced a significant decrease in the γ-aminobutyric acid content of the brain, resulting in induction of convulsions.