Groner Efrat, Ashani Yacov, Schorer-Apelbaum Donna, Sterling Jeffrey, Herzig Yaacov, Weinstock Marta
Department of Pharmacology, Hebrew University, Ein Kerem, Jerusalem 91120, Israel.
Mol Pharmacol. 2007 Jun;71(6):1610-7. doi: 10.1124/mol.107.033928. Epub 2007 Mar 8.
Controlled inhibition of brain acetyl- and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of the OH-derivatives of rasagiline or selegiline that can serve as inhibitors of MAO-B and as antioxidants. We conducted a detailed in vitro kinetic study on two series of novel N-methyl, N-alkyl carbamates and compared them with rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k(i)) and decarbamylation (k(r)) of recombinant human AChE were mainly determined by the size of the N-alkyl substituent and to a lesser extent by the nature of the leaving group. k(i) was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that k(i) depends on a delicate balance between the length of the residue and its degree of freedom of rotation. By contrast, presumably because of its wider gorge, inhibition of human BChE was less influenced by the size of the alkyl group and more dependent on the structure of the leaving group. The data show how the degree of enzyme inhibition can be manipulated by structural changes in the N-methyl, N-alkyl carbamates and the corresponding leaving group to achieve therapeutic levels of brain AChE, BChE, and MAO-B inhibition.
对大脑乙酰胆碱酯酶和丁酰胆碱酯酶（分别为AChE和BChE）以及单胺氧化酶-B（MAO-B）进行可控抑制，可能会减缓阿尔茨海默病和帕金森病中的神经退行性变。据推测，某些氨基甲酸酯会抑制AChE和BChE，同时在大脑中释放雷沙吉兰或司来吉兰的OH衍生物，这些衍生物可作为MAO-B的抑制剂和抗氧化剂。我们对两个系列的新型N-甲基、N-烷基氨基甲酸酯进行了详细的体外动力学研究，并将它们与已知的抗阿尔茨海默病药物卡巴拉汀进行了比较。重组人AChE的氨甲酰化速率（k(i)）和脱氨甲酰化速率（k(r)）主要由N-烷基取代基的大小决定，在较小程度上由离去基团的性质决定。当烷基为甲基、己基、环己基或芳基取代基时，k(i)最高，而当烷基为乙基时，k(i)最低。这表明k(i)取决于残基长度与其旋转自由度之间的微妙平衡。相比之下，大概是因为人BChE的活性中心峡谷更宽，其抑制作用受烷基大小的影响较小，而更多地取决于离去基团的结构。数据显示了如何通过N-甲基、N-烷基氨基甲酸酯及其相应离去基团的结构变化来控制酶抑制程度，以达到对大脑AChE、BChE和MAO-B抑制的治疗水平。
