Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer's disease
Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer's disease
复制标题
DOI：
10.1016/j.ejphar.2003.11.080
复制
发表时间：
2004-02-13
影响因子：
5
通讯作者：
White, WF
中科院分区：
文献类型：
--
作者：
Liston, DR;Nielsen, JA;White, WF
胆碱酯酶抑制剂对乙酰胆碱酯酶和丁基胆碱酯酶的选择性不同。我们检查了几种胆碱酯酶抑制剂，并评估了乙酰胆碱酯酶与丁基胆碱酯酶抑制在这些药物的中枢和外周反应中的相对作用。多奈哌齐和icopezil对乙酰胆碱酯酶有很高的选择性，而他克林和庚基生斯的明对丁基胆碱酯酶的选择性高于乙酰胆碱酯酶。这四种化合物都增加了小鼠大脑中乙酰胆碱的水平。对震颤（中枢效应）和流涎（外周效应）的剂量反应曲线显示，多奈哌齐和伊科吡齐比非选择性抑制剂他克林和heptylphysostomine具有更有利的治疗指标。选择性丁基胆碱酯酶抑制剂四异丙基焦磷酰胺（isoompa）的联合施用增强了选择性乙酰胆碱酯酶抑制剂icopezil的外周作用，而不是中枢作用。在小鼠中观察到的治疗指数的改善是由于乙酰胆碱酯酶与丁基胆碱酯酶的高度选择性，这表明乙酰胆碱酯酶的高选择性可能有助于多奈哌齐等药物在阿尔茨海默病患者的临床良好耐受性。(C) 2003 Elsevier B.V.版权所有
Cholinesterase inhibitors vary in their selectivity for acetylcholinesterase versus butyrylcholinesterase. We examined several cholinesterase inhibitors and assessed the relative role of acetylcholinesterase versus butyrylcholinesterase inhibition in central and peripheral responses to these medications. Donepezil and icopezil are highly selective for acetylcholinesterase,whereas tacrine and heptylphysostigmine demonstrated greater potency for butyrylcholinesterase over acetylcholinesterase. All four compounds increased acetylcholine levels in mouse brains. Dose-response curves for tremor (central effect) and salivation (peripheral effect) showed that donepezil and icopezil possess a more favourable therapeutic index than the nonselective inhibitors, tacrine and heptylphysostigmine. Co-administration of the selective butyrylcholinesterase inhibitor tetraisopropylpyrophosphoramide (iso-OMPA) potentiated peripheral, but not central, effects of the selective acetylcholinesterase inhibitor icopezil. The improved therapeutic index observed in mice with icopezil is due to a high degree of selectivity for acetylcholinesterase versus butyrylcholinesterase, suggesting that high selectivity for acetylcholinesterase may contribute to the clinically favourable tolerability profile of agents such as donepezil in Alzheimer's disease patients. (C) 2003 Elsevier B.V. All rights reserved.