Makhaeva G F, Filonenko I V, Yankovskaya V L, Fomicheva S B, Malygin V V
Laboratory of Pharmacology, Institute of Physiologically Active Substances, Russian Academy of Science, Chernogolovka, Moscow Region.
Neurotoxicology. 1998 Aug-Oct;19(4-5):623-8.
Acetylcholinesterase (AChE) and neuropathy target esterase (neurotoxic esterase, NTE) are two major target enzymes for organophosphorus (OP) esters. The relative potency of an OP ester to react with AChE or with NTE in vitro correlates with its relative potency in vivo to cause acute toxicity (death) or organopohosphate-induced delayed neurotoxicity (OPIDN). On this basis extrapolation from in vitro to in vivo data now seems justifiable to predict risk of OPIDN. The kinetics of NTE and AChE inhibition by experimental pesticides of the general formula (RO)2P(O)ON=CClCH2Cl, where R = methyl, ethyl, isopropyl, propyl, isobutyl, butyl, pentyl, has been studied. Compounds with short R (methyl, ethyl) were shown to be far more potent inhibitors of AChE than NTE. Both anti-NTE activity, selectivity for NTE and, correspondingly, the propensity of compounds to cause OPIDN rise with increasing their hydrophobicity. A high value of ki(NTE)/ki(AChE) for R = pentyl suggests that this compound would have the potential to cause OPIDN at doses lower than the LD50. A quantitative structure-activity relationships (QSAR) analysis indicated that NTE and AChE have different structural and electronic requirements for their respective OP inhibitors.
乙酰胆碱酯酶（AChE）和神经病变靶酯酶（神经毒性酯酶，NTE）是有机磷酸酯（OP）的两种主要靶标酶。一种OP酯在体外与AChE或NTE反应的相对效力与其在体内引起急性毒性（死亡）或有机磷酸酯诱导的迟发性神经毒性（OPIDN）的相对效力相关。在此基础上，现在从体外数据推断体内数据以预测OPIDN风险似乎是合理的。研究了通式为(RO)2P(O)ON=CClCH2Cl的实验性农药对NTE和AChE的抑制动力学，其中R = 甲基、乙基、异丙基、丙基、异丁基、丁基、戊基。结果表明，R为短链（甲基、乙基）的化合物对AChE的抑制作用远强于对NTE的抑制作用。随着化合物疏水性的增加，其抗NTE活性、对NTE的选择性以及相应地导致OPIDN的倾向均增加。R = 戊基时，ki(NTE)/ki(AChE)的值较高，表明该化合物在低于半数致死剂量（LD50）时可能导致OPIDN。定量构效关系（QSAR）分析表明，NTE和AChE对各自的OP抑制剂具有不同的结构和电子要求。
