Medicinal Chemistry Group, Chemistry Department, Military Institute of Engineering, Rio de Janeiro, Brazil.
Bioorg Med Chem. 2013 Sep 15;21(18):5923-30. doi: 10.1016/j.bmc.2013.05.063. Epub 2013 Jun 19.
Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). The control of ACh function is performed by its hydrolysis with AChE, a process that can be completely interrupted by inhibition of the enzyme by phosphylation with OPs. Compounds used for reactivation of the phosphylated AChE are cationic oximes, which usually possess low membrane and hematoencephalic barrier permeation. Neutral oximes possess a better capacity for hematoencephalic barrier permeation. NMR spectroscopy is a very confident method for monitoring the inhibition and reactivation of enzymes, different from the Ellman test, which is the common method for evaluation of inhibition and reactivation of AChE. In this work (1)H NMR was used to test the effect of neutral oximes on inhibition of AChE and reactivation of AChE inhibited with ethyl-paraoxon. The results confirmed that NMR is a very efficient method for monitoring the action of AChE, showing that neutral oximes, which display a significant AChE inhibition activity, are potential drugs for Alzheimer disease. The NMR method showed that a neutral oxime, previously indicated by the Ellman test as better in vitro reactivator of AChE inhibited with paraoxon than pralidoxime (2-PAM), was much less efficient than 2-PAM, confirming that NMR is a better method than the Ellman test.
神经毒有机磷化合物（OPs）被用作农药和化学战剂，每年导致全球超过 70 万人中毒。OPs 的主要靶标是乙酰胆碱酯酶（AChE）的抑制，AChE 是控制神经递质乙酰胆碱（ACh）的必需酶。ACh 功能的控制是通过 AChE 将其水解来完成的，该过程可被 OPs 的磷酰化完全中断。用于重新激活磷酰化 AChE 的化合物是阳离子肟，其通常具有较低的膜和血脑屏障通透性。中性肟具有更好的血脑屏障通透性。NMR 光谱是一种非常有信心的监测酶抑制和复活的方法，与 Ellman 试验不同，Ellman 试验是评估 AChE 抑制和复活的常用方法。在这项工作中，（1）H NMR 用于测试中性肟对 AChE 抑制和乙基-对氧磷抑制的 AChE 复活的影响。结果证实 NMR 是监测 AChE 作用的非常有效的方法，表明显示出显著的 AChE 抑制活性的中性肟是阿尔茨海默病的潜在药物。NMR 方法表明，一种先前通过 Ellman 试验表明比氯解磷定（2-PAM）更好的体外 AChE 抑制剂对氧磷抑制的中性肟，其效率远低于 2-PAM，这证实了 NMR 是比 Ellman 试验更好的方法。
