Eel acetylcholinesterase inhibition studies with heteroarylphosphinates |
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Authors: | Claire N. Lieske James H. Clark Howard G. Meyer Leigh Boldt Martin D. Green John R. Lowe Walter E. Sultan Peter Blumbergs Matthew A. Priest |
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Affiliation: | 1. U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA;2. Ash Stevens, Inc., Detroit, Michigan 48202 USA |
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Abstract: | The inhibition of eel acetylcholinesterase by the 4-nitrophenyl esters of 2-furyl(methyl)-, methyl(2-thienyl)-, di-2-furyl-, and di-2-thienylphosphinic acid (I, II, III, and IV, respectively) was investigated at pH 6.90 in 0.067 M phosphate buffer (25.0°C) using stopped-flow instrumentation and automated data processing. Our evaluation of the dissociation constant, Kd, the unimolecular bonding rate constant, k2, and the bimolecular reaction constant, ki, are the first reported values for these constants for alkyl/heteroaryl and diheteroaryl esters of phosphinic acids. The largest ki value (19,330 M?1 sec?1) was observed for the reaction of I with the enzyme. The order for the remaining three is II > IV > III. There is no direct relationship between the hydrolysis rates of the esters and their anticholinesterase activities on eel acetylcholinesterase. Likewise, there is no direct relationship between their anticholinesterase activities and the LD50 values in rats. |
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