Lin Gialih, Lee Yu-Ru, Liu Yu-Chen, Wu Yon-Gi
Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan.
Chem Res Toxicol. 2005 Jul;18(7):1124-31. doi: 10.1021/tx050014o.
Phenyl carbamates are used to treat Alzheimer's disease. These compounds inhibit acetylcholinesterase and butyrylcholinesterase. The goal of this work was to determine the chemical characteristics of ortho substituents that make some carbamates better inhibitors of butyrylcholinesterase than of acetylcholinesterase, cholesterol esterase, and lipase. The inhibition constants, Ki, Ki', kc, and ki 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 butyrylcholinesterase 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 butyrylcholinesterase by ortho polar effects. Conformations of enzyme-inhibitor tetrahedral intermediates for butyrylcholinesterase 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 acetylcholinesterase.
苯基氨基甲酸酯用于治疗阿尔茨海默病。这些化合物可抑制乙酰胆碱酯酶和丁酰胆碱酯酶。本研究的目的是确定邻位取代基的化学特性，这些特性使得某些氨基甲酸酯成为比乙酰胆碱酯酶、胆固醇酯酶和脂肪酶更好的丁酰胆碱酯酶抑制剂。测定了九种不同氨基甲酸酯的抑制常数Ki、Ki'、kc和ki。根据哈米特方程、塔夫脱-库特-汉斯奇方程和斯旺-卢普顿方程绘制这些值，以获得将取代基的化学性质与抑制效力相关联的常数。研究发现，抑制剂的邻位吸电子取代基在丁酰胆碱酯酶中比在乙酰胆碱酯酶中更能稳定四面体中间体的负电荷。这一结果证实了丁酰胆碱酯酶的氧阴离子空穴形成三齿氢键，而乙酰胆碱酯酶的氧阴离子空穴形成双齿氢键。此外，还发现抑制剂的邻位供电子取代基通过邻位极性效应加速了对丁酰胆碱酯酶的抑制。丁酰胆碱酯酶的酶-抑制剂四面体中间体的构象与乙酰胆碱酯酶和胆固醇酯酶的不同；四面体中间体中的邻位取代基在丁酰胆碱酯酶中远离带负电荷的羰基氧，但在乙酰胆碱酯酶和胆固醇酯酶中靠近带负电荷的羰基氧。总之，邻位供电子取代基是比乙酰胆碱酯酶更好的丁酰胆碱酯酶抑制剂，而吸电子取代基是更好的乙酰胆碱酯酶抑制剂。
