Randall J C, Ambroso J L, Groutas W C, Brubaker M J, Richardson R J
Department of Environmental and Industrial Health, School of Public Health, University of Michigan, Ann Arbor 48109, USA.
Toxicol Appl Pharmacol. 1997 Mar;143(1):173-8. doi: 10.1006/taap.1996.8082.
Carbamyl sulfonate (CS) compounds are a novel class of carbamates derived from amino acid methyl esters. They have the general structure RCH(COOCH3)NH(CO)SO-3K+, where R is the sidechain of the parent amino acid. These compounds were developed as active site-directed inhibitors of human leukocyte elastase (HLE). The purpose of this study was to characterize the inhibition of hen brain neurotoxic esterase (neuropathy target esterase, NTE), horse serum butyrylcholinesterase (BuChE), and bovine erythrocyte acetylcholinesterase (AChE) by CS analogs derived from the methyl esters of L-ala, D-norval, L-norval, L-phe, L-val, L-norleu, D-met, and L-met. Bimolecular rate constants of inhibition (ki) for NTE ranged from 0.571 for L-ala-CS to 17.7 mM-1 min-1 for L-norleu-CS (10-min I50 values of 123 and 3.92 microM, respectively). Potency against NTE increased with chain length for straight-chain R-groups of L-CS compounds. Unlike HLE, NTE was only weakly stereoselective for CS compound enantiomers. The L-isomers were weaker inhibitors of BuChE than NTE (10-min I50 range of 742 to 35.6 microM). In contrast to the L-enantiomers, the I50 plots of D-met-CS and D-norval-CS were not linear for BuChE, suggesting a possible stereospecific mechanistic shift for inhibition of this enzyme, AChE was not effectively inhibited by any of the CS compounds (I50 values > 750 microM). The specificity and charged nature of CS compounds give these unusual NTE inhibitors potential advantages for mechanistic studies of organophosphorus compound-induced delayed neurotoxicity (OPIDN) and its protection or potentiation.
氨甲酰磺酸酯（CS）化合物是一类新型的氨基甲酸酯，由氨基酸甲酯衍生而来。它们具有通式RCH(COOCH3)NH(CO)SO-3K+，其中R是母体氨基酸的侧链。这些化合物被开发为人白细胞弹性蛋白酶（HLE）的活性位点定向抑制剂。本研究的目的是表征由L-丙氨酸、D-正缬氨酸、L-正缬氨酸、L-苯丙氨酸、L-缬氨酸、L-正亮氨酸、D-蛋氨酸和L-蛋氨酸甲酯衍生的CS类似物对鸡脑神经毒性酯酶（神经病变靶标酯酶，NTE）、马血清丁酰胆碱酯酶（BuChE）和牛红细胞乙酰胆碱酯酶（AChE）的抑制作用。NTE的双分子抑制速率常数（ki）范围从L-丙氨酸-CS的0.571到L-正亮氨酸-CS的17.7 mM-1 min-1（10分钟I50值分别为123和3.92 microM）。对于L-CS化合物的直链R基团，对NTE的效力随链长增加而增强。与HLE不同，NTE对CS化合物对映体的立体选择性较弱。L-异构体对BuChE的抑制作用比NTE弱（10分钟I50范围为742至35.6 microM）。与L-对映体相反，D-蛋氨酸-CS和D-正缬氨酸-CS对BuChE的I50曲线不是线性的，这表明抑制该酶可能存在立体特异性机制转变。任何CS化合物均未有效抑制AChE（I50值>750 microM）。CS化合物的特异性和带电性质为这些不同寻常的NTE抑制剂在有机磷化合物诱导的迟发性神经毒性（OPIDN）及其保护或增强作用的机制研究中提供了潜在优势。
