Inhibition of brain glutamate decarboxylase by 4,5-dihydroxyisophthalic acid and related compounds.
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 microM. The inhibition of these compounds was competitive with respect to L-glutamate. The Ki values were 0.02, 1.2 and 4.9 microM 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 gamma-aminobutyric acid content of the brain, resulting in induction of convulsions.
D000818:Animals; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors*; D062385:Hydroxybenzoates / Q000494:pharmacology*; D051379:Mice; D010795:Phthalic Acids / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D062385:Hydroxybenzoates; D010795:Phthalic Acids; C015820:4,5-dihydroxyisophthalic acid; D005680:gamma-Aminobutyric Acid; D002262:Carboxy-Lyases; D005968:Glutamate Decarboxylase