作为乙酰胆碱酯酶准底物抑制剂的氟化醛和酮。

Fluorinated aldehydes and ketones acting as quasi-substrate inhibitors of acetylcholinesterase.

Brodbeck U, Schweikert K, Gentinetta R, Rottenberg M

Biochim Biophys Acta. 1979 Apr 12;567(2):357-69. doi: 10.1016/0005-2744(79)90122-0.

Abstract

The inhibition of acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) by compounds containing trifluoromethyl-carbonyl groups was investigated and related to the effects observed with structurally similar, non-fluorinated chemicals. 2. Compounds that in aqueous solution readily form hydrates inhibit acetylcholinesterase in a time-dependent process. On the other hand non-hydrated, carbonyl-containing compounds showed rapid and reversible, time-independent enzyme inactivation when assayed under steady state conditions. 3. m-N,N,N-Trimethylammonium-acetophenone acts as a rapid and reversible, time-independent, linear competitive inhibitor of acetylcholinesterase (Ki = 5.0 . 10(-7) M). 4. The most potent enzyme inhibitor tested in this series was N,N,N,-trimethylammonium-m-trifluoroacetophenone. It gives time-dependent inhibition and the concentration which inactivates eel acetylcholinesterase to 50% of the original activity after 30 min exposure is 1.3 . 10(-8) M. The bimolecular rate constant for this reaction is 1.8 . 10(6) 1 . mol-1 . min-1. The enzyme-inhibitor complex is very stable as the inhibited enzyme after 8 days of dialysis is reactivated to 20% only. This compound represents a quasi-substrate inhibitor of acetylcholinesterase.

摘要

研究了含三氟甲基羰基的化合物对乙酰胆碱酯酶（乙酰胆碱水解酶，EC 3.1.1.7）的抑制作用，并将其与结构相似的非氟化化学品所观察到的效应进行关联。2. 在水溶液中容易形成水合物的化合物在一个时间依赖性过程中抑制乙酰胆碱酯酶。另一方面，非水合的含羰基化合物在稳态条件下测定时表现出快速且可逆的、与时间无关的酶失活。3. 间-N,N,N-三甲基铵苯乙酮作为乙酰胆碱酯酶的快速且可逆的、与时间无关的线性竞争性抑制剂（Ki = 5.0×10⁻⁷ M）。4. 该系列中测试的最有效的酶抑制剂是N,N,N-三甲基铵间三氟苯乙酮。它产生时间依赖性抑制，在暴露30分钟后使鳗鱼乙酰胆碱酯酶失活至原始活性50%的浓度为1.3×10⁻⁸ M。该反应的双分子速率常数为1.8×10⁶ 1·mol⁻¹·min⁻¹。酶 - 抑制剂复合物非常稳定，因为透析8天后的被抑制酶仅被重新激活至20%。该化合物代表乙酰胆碱酯酶的一种准底物抑制剂。