Khalid Asaad, Anjum Shazia, Khan M Riaz, Choudhary M Iqbal
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi 75270, Pakistan.
Bioorg Med Chem. 2004 May 1;12(9):1995-2003. doi: 10.1016/j.bmc.2004.03.002.
The mechanism of inhibition of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) enzymes by 23 pregnane-type alkaloids isolated from the Sarcococca saligna was investigated. Lineweaver-Burk and Dixon plots and their secondary replots showed that the majority of these compounds, that is 1, 4, 5, 6, 9, 10, 12, 13, 15-19, and 21 were found to be noncompetitive inhibitors of both enzymes. Compounds 8, 20, 22, and 23 were determined to be uncompetitive inhibitors of BChE, while compounds 11 and 14 were found to be uncompetitive and linear mixed inhibitors of AChE, respectively. Ki values were found to be in the range of 2.65-250.0 microM against AChE and 1.63-30.0 microM against BChE. The structure-activity relationship (SAR) studies suggested that the major interaction of the enzyme-inhibitor complexes are due to hydrophobic and cation-pi interactions inside the aromatic gorge of these cholinesterases. The effects of various substituents on the activity of these compounds are also discussed in details.
研究了从清香桂中分离出的23种孕烷型生物碱对乙酰胆碱酯酶（AChE，EC 3.1.1.7）和丁酰胆碱酯酶（BChE，EC 3.1.1.8）的抑制机制。Lineweaver-Burk图和Dixon图及其二次重绘图表明，这些化合物中的大多数，即1、4、5、6、9、10、12、13、15 - 19和21，被发现是这两种酶的非竞争性抑制剂。化合物8、20、22和23被确定为BChE的非竞争性抑制剂，而化合物11和14分别被发现是AChE的非竞争性和线性混合型抑制剂。发现对AChE的Ki值在2.65 - 250.0微摩尔范围内，对BChE的Ki值在1.63 - 30.0微摩尔范围内。构效关系（SAR）研究表明，酶 - 抑制剂复合物的主要相互作用是由于这些胆碱酯酶芳香峡谷内的疏水和阳离子 - π相互作用。还详细讨论了各种取代基对这些化合物活性的影响。
