Molecular Pharmacology, Vol 9, 172-177, Copyright © 1973 by the American Society for Pharmacology and Experimental Therapeutics

Analogues of Fusaric (5-Butylpicolinic) Acid as Potent Inhibitors of Dopamine -Hydroxylase

¹ Department of Biochemistry, Institute for Developmental Research, Aichi Prefecture Colony, Kasugai, Aichi, Japan

Several derivatives of picolinic acid were effective inhibitors of a purified bovine adrenal dopamine -hydroxylase [3,4-dihydroxyphenylethylamine, ascorbate:oxygen oxidoreductase (hydroxylating), EC 1.14.2.1]. Inhibition of the enzyme by derivatives of picolinic acid was uncompetitive with the substrate and competitive with ascorbic acid. Among the derivatives of picolinic acid tested, 5-(3',4'-dihalobutyl)picolinic acid and 5-(3'-halobutyl) picolinic acid were the most potent inhibitors of the hydroxylase, producing 50% inhibition at a concentration of 10 nM. While 5-butylpicolinic acid seemed to have the highest stability constant of the copper chelate among the picolinic acids tested, its inhibitory activity was not the strongest. There was no correlation between the copper-chelating capacity of the picolinic acids and their inhibitory effects on the enzyme. Diethyldithiocarbamate, which is a more effective copper-chelating agent than 5-butylpicolinic acid was a less potent enzyme inhibitor. These data indicate that the inhibition of dopamine -hydroxylase by picolinic acids was not primarily due to the chelate formation between the compounds and copper of the enzyme. Some of these picolinic acids seemed to be specific inhibitors of the hydroxylase and did not inhibit tyrosinase, a copper-containing enzyme, up to 10,000 times the concentration effectively inhibitory to dopamine -hydroxylase.

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ACKNOWLEDGMENTS The authors are grateful to Dr. I. Matsumoto and Dr. T. Miyano (Banyu Pharmaceutical Company, Ltd.) for help in preparing the picolinic acids. They also thank Dr. K. Suzuki (Department of Inorganic Chemistry, Faculty of Science, University of Nagoya) and Dr. K. Samejima (Department of Analytical Chemistry, Faculty of Pharmaceutical Science, University of Tokyo) for their helpful advice on the copper chelate study.