Molecular recognition by acetylcholinesterase at the peripheral anionic site: structure–activity relationships for inhibitions by aryl carbamates Original Research Article

Substituted phenyl-N-butyl carbamates () are potent irreversible inhibitors of Electrophorus electricus acetylcholinesterase. Carbamates act as the peripheral anionic site-directed irreversible inhibitors of acetylcholinesterase by the stop-time assay in the presence of a competitive inhibitor, edrophonium. Linear relationships between the logarithms of the dissociation constant of the enzyme–inhibitor adduct (Ki), the inactivation constant of the enzyme–inhibitor adduct (k2), and the bimolecular inhibition constant (ki) for the inhibition of Electrophorus electricus acetylcholinesterase by carbamates and the Hammett substituent constant (σ), are observed, and the reaction constants (ρs) are −1.36, 0.35 and −1.01, respectively. Therefore, the above reaction may form a positive charged enzyme–inhibitor intermediate at the peripheral anionic site of the enzyme and may follow the irreversible inactivation by a conformational change of the enzyme.