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首页> 外文期刊>Biochemical Pharmacology >Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators.
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Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators.

机译：阳离子膦酰基肟对胆碱酯酶的抑制作用突出了季肟活化剂带电吡啶基的独特性质。

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摘要

Oxime-induced reactivation of phosphonylated cholinesterases (ChEs) produces charged phosphonyl pyridine oxime intermediates (POXs) that are most potent organophosphate (OP) inhibitors of ChEs. To understand the role of cationic pyridine oxime leaving groups in the enhanced anti-ChE activity of POXs, the bimolecular rate constants for the inhibition (k(i)) of acetylcholinesterases (AChE) and butyrylcholinesterases (BChE), and the rate of decomposition (k(d)) of authentic O-alkyl methylphosphonyl pyridine oximes (AlkMeP-POXs) and N,N-dimethylamidophosphoryl pyridine oximes (EDMP-POXs), were studied. Stability ranking order in aqueous solutions correlated well with the electronic features and optimized geometries that were obtained by ab initio calculations at 6-31G(**) basis set level. AlkMeP-POXs of the 2-pyridine oxime series were found to be 4- to 8-fold more stable (t(1/2)=0.7 to 1.5 min) than the homologous O,O-diethylphosphoryl (DEP) oxime. Results suggest that re-inhibition of enzyme activity by POX is less likely during the reactivation of DEP-ChEs (obtained by use of DEP-containing pesticides) by certain oximes, compared to nerve agent-inhibited ChEs. The greatest inhibition was observed for the O-cyclohexyl methylphosphonyl-2PAM derivative (4.0 x 10(9)M(-1)min(-1); mouse AChE) and is 10-fold higher than the k(i) of cyclosarin. Increasing the size of the O-alkyl substituent of AlkMeP-POXs had only a small to moderate effect on the k(i) of ChEs, signifying a major role for the cationic pyridine oxime leaving group in the inhibition reaction. The shape of plots of logk(i) vs. pK(a) of the leaving groups for AlkMeP-PAMs and DEP-PAMs, could be used as a diagnostic tool to highlight and rationalize the unique properties of the cationic moiety of pyridine oxime reactivators.
机译：肟诱导的磷酸化胆碱酯酶（ChEs）的再活化产生带电荷的膦酰基吡啶肟肟中间体（POX），是最有效的ChEs有机磷酸酯（OP）抑制剂。要了解阳离子吡啶肟离去基团在增强POX的抗ChE活性中的作用，抑制乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的双分子速率常数（k（i））以及分解速率（研究了真实的O-烷基甲基膦酰基吡啶肟（AlkMeP-POXs）和N，N-二甲基酰胺基磷酰基吡啶肟（EDMP-POXs）的k（d）。水溶液中的稳定性排名顺序与电子特征和优化的几何形状密切相关，这些电子特征和优化的几何形状是通过从头算在6-31G（**）的基础水平上获得的。发现2-吡啶肟系列的AlkMeP-POX比同源的O，O-二乙基磷酰基（DEP）肟稳定4至8倍（t（1/2）= 0.7至1.5分钟）。结果表明，与抑制神经毒剂的ChEs相比，某些肟在DEP-ChEs（通过使用含DEP的农药获得）的再活化过程中，POX对酶活性的重新抑制可能性较小。观察到最大的抑制作用为O-环己基甲基膦酰基-2PAM衍生物（4.0 x 10（9）M（-1）min（-1）;小鼠AChE），它比环沙林的k（i）高10倍。增加AlkMeP-POX的O-烷基取代基的大小仅对ChEs的k（i）产生小到中等的影响，这表明阳离子吡啶肟肟离去基团在抑制反应中起主要作用。 AlkMeP-PAM和DEP-PAM的离去基团的logk（i）对pK（a）的图的形状可以用作诊断工具，以突出并合理化吡啶肟活化剂的阳离子部分的独特性质。

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