Inhibition of acetylcholinesterase by derivatives of 1,3,2-dioxaphosphorinane 2-oxide

Abstract

Cholinesterases are inhibited by 2-fluoro-1,3,2-dioxaphosphorinane 2-oxide by a mechanism that involves a slow association step followed by a very slow phosphorylation step. No phosphorylation step was observed for the interaction between acetylcholinesterase and 2-S-[2'-(NN-diethylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide.

Formation of an unstable covalent intermediate during the inhibition of electric-eel acetylcholinesterase with 1,3,2-dioxaphosphorinane 2-oxides

“…In contrast with Coult's (1976) findings, in a previous report, no biphasic profile could be detected during the inhibition of acetylcholinesterase by compound (I) provided that the inhibitor was preincubated in buffered aqueous solution for 20min before the addition of the enzyme (Ashani et al, 1972).…”

“…It is generally accepted that the formation of the enzyme-inhibitor reversible complex and its dissociation occur very rapidly. However, the rate constants expressing the velocities of the complex-formation and its dissociation (3 x 103M-1 min-' and 4 x 10-2 min-' respectively) reported by Coult (1976) are surprisingly low. Such values suggest an extremely unusual property of a specific inhibitor (I) and perhaps one should reconsider the mechanistic interpretation of many other kinetic observations where the inhibition of acetylcholinesterase by various organophosphorus esters and carbamates were investigated extensively.…”

“…It has been reported recently that the reaction of acetylcholinesterase (EC 3.1.1.7) and 2-fluoro-1,3,2-dioxaphosphorinane 2-oxide (I) is a progressive inhibition, characterized by a biphasic kinetic profile (Coult, 1976). It was explained by the author that the first phase represents slow formation of a reversible complex approaching a steady-state equilibrium, whereas the second phase is significantly slower (approx.…”

“…by one order of magnitude), and represents the subsequent phosphorylation step. Consequently, according to Coult (1976), the slow return of enzyme activity on dilution is due to dissociation of a reversible complex, rather than hydrolysis of phosphorylated enzyme.…”

“…Such values suggest an extremely unusual property of a specific inhibitor (I) and perhaps one should reconsider the mechanistic interpretation of many other kinetic observations where the inhibition of acetylcholinesterase by various organophosphorus esters and carbamates were investigated extensively. It is difficult to refer in more detail to Coult's (1976) work owing to insufficient details with respect to the experimental procedures and the rationale behind the mathematical solution of the kinetic schemes.…”