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Molecular Pharmacology, Vol 3, 225-232, Copyright © 1967 by the American Society for Pharmacology and Experimental Therapeutics

The Reaction of Acetylcholinesterase with Diethylphosphoryl Esters of Quaternary and Tertiary Aminophenols

RICHARD J. KITZ 1, SARA GINSBURG 1, and IRWIN B. WILSON 1

1 Departments of Anesthesiology, Biochemistry and Neurology, Columbia University, College of Physicians and Surgeons, New York, New York 10032

The second order rate constant values were measured for the inhibition of acetylcholinesterase (electric eel) by a number of diethylphosphoryl esters (anhydrides) containing different leaving groups. These groups include the tertiary, quaternary, and some diquaternary derivatives of hydroxyquinoline, hydroxyisoquinoline, hydroxystilbazole, and hydroxyphenylazopyridine. The values of the rate constants for the uncharged inhibitors formed a monotonic sequence when plotted against the value of the pKa of the leaving group. As the pKa value of the leaving group increased, the rate fell slowly at first but then very rapidly as the pKa value exceeded 7-8. The cationic inhibitors, except for two compounds, were far more active than would be expected for the pKa values of the leaving groups, and it was concluded therefore that these inhibitors were more active because they were attracted to the enzyme by the anionic site.

Note:
ACKNOWLEDGMENT This work was supported by the Division of Research Grants and Fellowships, National Institutes of Health, Grant NB 00573-18 and Program Project Grant GM-09069-04 and by National Science Foundation Grant GB 2817.

Submitted on November 28, 1966
Revised on February 16, 1967




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