Ogura H, Kosasa T, Kuriya Y, Yamanishi Y
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Methods Find Exp Clin Pharmacol. 2000 Oct;22(8):609-13. doi: 10.1358/mf.2000.22.8.701373.
This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.
本研究旨在比较多奈哌齐与其他一些已开发用于治疗阿尔茨海默病的胆碱酯酶（ChE）抑制剂对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的体外抑制作用。氨基甲酸酯衍生物毒扁豆碱和卡巴拉汀需要预孵育才能表现出适当的抗ChE活性。毒扁豆碱在30 - 60分钟内产生最大ChE抑制作用，而卡巴拉汀对AChE和BuChE活性的抑制作用分别在48小时和6小时后达到峰值。在每种ChE抑制剂的最佳测定条件下，对AChE活性的抑制效力（IC50）顺序为：毒扁豆碱（0.67 nM）>卡巴拉汀（4.3 nM）>多奈哌齐（6.7 nM）>TAK - 147（12 nM）>他克林（77 nM）>茚达卡林（270 nM）。苄基哌啶衍生物多奈哌齐和TAK - 147对AChE的选择性高于BuChE。氨基甲酸酯衍生物表现出中等选择性，而4 - 氨基吡啶衍生物他克林和茚达卡林则无选择性。这些ChE抑制剂对AChE活性的抑制效力可能说明它们在体内的潜在活性。
