CATECHOL-O-METHYLTRANSFERASE. II. A NEW CLASS OF INHIBITORS OF CATECHOL-O-METHYLTRANSFERASE; 3,5-DIHYDROXY-4-METHOXYBENZOIC ACID AND RELATED COMPOUNDS

¹ Laboratory of Chemistry, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland

A class of compounds related in the aromatic ring to 3,5-dihydroxy-4-methoxy- and 3-hy-droxy-4,5-dimethoxybenzoic acids have been shown to be inhibitors in vitro and in vivo of catechol-O-methyltnansfenase. A study of the structure-activity relationship of a series of compounds with this ring structure is presented delineating structural modifications of this class of inhibitors. The most effective inhibitors were the parent substituted benzenes, the benzoic acids and the phenethylamines. The benzoic acid derivatives were nontoxic and virtually 100% inhibition of mouse liver catechol-O-methyltransferase could be achieved for 45 minutes with a dose of 500 mg/kg. A kinetic analysis of the inhibition indicated a noncompetitive on mixed type of inhibition against various substrates and S-adenosyl-l-methionine. A complex relationship was demonstrated between magnesium ion concentration, inhibition and enzyme activity. Inhibition was greatest at an optimum magnesium ion concentration of 1.2 x 10^-3 M.

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