Molecular recognition by acetylcholinesterase at the peripheral anionic site : Structure-activity relationships for inhibitions by aryl carbamates

• Published in: Bioorganic & medicinal chemistry Vol. 7; no. 12; pp. 2683 - 2689
• Main Authors: GIALIH LIN, LAI, C.-Y, LIAO, W.-C
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.12.1999
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Animals; Anions; Biological and medical sciences; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Catalytic Domain; Cholinergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Edrophonium - pharmacology; Electrophorus; In Vitro Techniques; Kinetics; Magnetic Resonance Spectroscopy; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Conformation; Structure-Activity Relationship; Enzyme; Enzyme inhibitor; Esterases; Inhibitor enzyme complex; Acetylcholinesterase; Organic carbamate; In vitro; Hammett constant; Carboxylic ester hydrolases; Anionic site; Structure activity relation; Hydrolases; Aromatic compound; Mechanism of action; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(99)00213-8

Substituted phenyl-N-butyl carbamates (1-9) are potent irreversible inhibitors of Electrophorus electricus acetylcholinesterase. Carbamates 1-9 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 (k(i)) for the inhibition of Electrophorus electricus acetylcholinesterase by carbamates 1-9 and the Hammett substituent constant (sigma), are observed, and the reaction constants (ps) 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.