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標題: Ortho effects for inhibition mechanisms of butyrylcholinesterase by o-substituted phenyl N-butyl carbamates and comparison with acetylcholinesterase, cholesterol esterase, and lipase
作者: Lin, G.L.
Lee, Y.R.
Liu, Y.C.
Wu, Y.G.
關鍵字: structure-reactivity relationships;steady-state kinetics;molecular;recognition;alzheimers-disease;site;cholinesterases;binding;hydrolysis;rivastigmine;substrate
Project: Chemical Research in Toxicology
期刊/報告no:: Chemical Research in Toxicology, Volume 18, Issue 7, Page(s) 1124-1131.
Phenyl carbamates are used to treat Alzheimer's disease. These compounds inhibit acetyleholinesterase and butyrylcholinesterase. The goal of this work was to determine the chemical characteristics of ortho substituents that make some carbamates better inhibitors of butyryleholinesterase than of acetylcholinesterase, cholesterol esterase, and lipase. The inhibition constants, K(i), K(i)('), k(c), and k(i) were measured for nine different carbamates. The values were plotted according to Hammett, Taft-Kutter-Hansch, and Swan-Lupton to obtain constants that correlated the chemical nature of the substituents with inhibition potency. It was found that the negative charges of tetrahedral intermediates were more stabilized by ortho electron-withdrawing substituents of the inhibitors in butyrylcholinesterase than in acetylcholinesterase. This result confirmed formation of 3-pronged hydrogen bonds for the oxyanion hole of butyryleholinesterase and 2-pronged hydrogen bonds for the oxyanion hole of acetylcholinesterase. Furthermore, it was found that ortho electron-donating substituents of the inhibitors accelerated inhibition of butyryleholinesterase by ortho polar effects. Conformations of enzyme-inhibitor tetrahedral intermediates for butyryleholinesterase were different from those for acetylcholinesterase and cholesterol esterase; ortho substituents in the tetrahedral intermediates were located far from the negatively charged carbonyl oxygens in butyrylcholinesterase, but close to the negatively charged carbonyl oxygens in acetylcholinesterase and cholesterol esterase. In conclusion, electron-donating substituents in the ortho position were better inhibitors of butyrylcholinesterase than acetylcholinesterase, while electron-withdrawing substituents were better inhibitors of acetyleholinesterase.
ISSN: 0893-228X
DOI: 10.1021/tx050014o
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