比较使用新型吡啶𬭩肟类化合物修饰的结构不同的有机磷酸酯的乙酰胆碱酯酶的复活率。
Comparison of the reactivation rates of acetylcholinesterase modified by structurally different organophosphates using novel pyridinium oximes.
机构信息
The Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT, 59812, USA; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
The Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT, 59812, USA.
出版信息
Environ Toxicol Pharmacol. 2019 Oct;71:103218. doi: 10.1016/j.etap.2019.103218. Epub 2019 Jul 5.
A novel panel of oximes were synthesized, which have displayed varying degree of reactivation ability towards different organophosphorus (OP) modified cholinesterases. In the present article, we report a comparative reactivation profile of a series of quaternary pyridinium-oximes for electric eel acetylcholinesterase (EEAChE) inhibited by the organophosphorus (OP) inhibitors methyl paraoxon (MePOX), ethyl paraoxon (POX; paraoxon) and diisopropyl fluorophosphate (DFP) that are distinguishable as dimethoxyphosphoryl, diethoxyphosphoryl and diisopropoxyphosphoryl AChE-OP-adducts. Most of the 59-oximes tested led to faster and more extensive reactivation of MePOX- and POX-inhibited EEAChE as compared to DFP-modified EEAChE. All were effective reactivators of three OP-modified EEAChE conjugates showing 18-21% reactivation for DFP-inhibited AChE and ≥45% reactivation for MePOX- and POX-inhibited EEAChE. Oximes 7 and 8 showed k values better than pralidoxime (1) for DFP-inhibited EEAChE. Reactivation rates determined at different inhibition times showed no significant change in k values during 0-90 min incubation with three OPs. However, a 34-72% decrease in k for MePOX and POX and > 95% decrease in k for DFP-inhibited EEAChE was observed after 24 h of OP-exposure (aging).
合成了一种新型肟类化合物，其对不同的有机磷（OP）修饰的胆碱酯酶具有不同程度的重激活能力。在本文中，我们报告了一系列季铵吡啶肟类化合物对电鳐乙酰胆碱酯酶（EEAChE）的复能作用的比较研究，电鳐乙酰胆碱酯酶被有机磷（OP）抑制剂甲基对氧磷（MePOX）、乙基对氧磷（POX；对氧磷）和二异丙基氟磷酸酯（DFP）抑制，这些抑制剂可区分出二烷氧基膦酰基、二乙氧基膦酰基和二异丙氧基膦酰基 AChE-OP 加合物。与 DFP 修饰的 EEAChE 相比，测试的 59 种肟类化合物中的大多数都能更快、更广泛地使 MePOX 和 POX 抑制的 EEAChE 重新激活。所有肟类化合物均能有效重新激活三种 OP 修饰的 EEAChE 缀合物，对 DFP 抑制的 AChE 显示 18-21%的复能率，对 MePOX 和 POX 抑制的 EEAChE 的复能率≥45%。肟类化合物 7 和 8对 DFP 抑制的 EEAChE 的 k 值优于氯解磷定（1）。在不同的抑制时间下测定的复能速率表明，在与三种 OP 孵育 0-90 分钟期间，k 值没有明显变化。然而，在 24 小时 OP 暴露（老化）后，MePOX 和 POX 的 k 值下降了 34-72%，而 DFP 抑制的 EEAChE 的 k 值下降了>95%。
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