Mechanism of inhibition reaction of acetylcholinesterase by phenyl N-methylcarbamates : Separation of hydrophobic, electronic, hydrogen bonding and proximity effects of aromatic substituents

Abstract

The association equilibrium constant, 1 K d , and the carbamylation constant, k 2, of 53 o-, m-, and p-substituted phenyl N-methylcarbamates with bovine erythrocyte acetylcholinesterase were determined. The 1 K d value varied 1000-fold, whereas the k 2 value did not depend upon the nature and position of substituents. The variation in log( 1 K d ) was analyzed using free energy related substituent parameters and regression analyses. The effect of substituents at o-, m-, and p-positions was nicely separated into hydrophobic, electronic, hydrogen bonding, and proximity (steric and field electronic for o-substituents) factors. The physicochemical significance of these factors was established by comparison with those for model organic reactivities. The mechanism of the whole reaction process was elucidated in terms of physical organic chemistry.