The inhibition of acetylcholinesterase by organophosphorus compounds containing a PCl bond

Abstract

1. 1. The inhibition of acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) from electrophorus by a number of substituted phosphono- and phosphoro- mono and dichloridates was studied. Rate constants were determined for both the inhibition of the enzyme and the spontaneous hydrolysis of the inhibitors; the two parameters could be evaluated even when the half time for hydrolysis of the inhibitor was less than 1 s. 2. 2. The second-order rate constants (ki) for enzyme inhibition were higher than 107 M-1·min-1 for most of the chloridates used; it was as high as 3·109 M-1·min-1 for phenyl phosphorodichloridate. No correlation was found between ki and the rates of hydrolysis of the inhibitors used. 3. 3. Isopropyl methyl phosphonochloridate was only six times more potent as an inhibitor than the corresponding fluoridate (i.e. sarin) although the rate of hydrolysis of the former compound is at least 5000 times higher. In contrast, methyl phosphonodichloridate was considerably more potent than the difluoridate. 4. 4. The rate of phosphorylation of the enzyme by the inhibitors was decreased in the presence of reversible cholinesterase inhibitors such as substituted quaternary ammonium compounds. 5. 5. The enzyme inhibited by dichloridates was not reactivatable. It is an "aged" enzyme. 6. 6. The diphenyl phosphoryl enzyme reactivates spontaneously and rapidly. It alsfages rapidly. © 1974.