City University of New York Hunter College, Department of Chemistry, New York, NY 10065, USA.
J Enzyme Inhib Med Chem. 2011 Feb;26(1):46-55. doi: 10.3109/14756361003671078. Epub 2010 Jun 28.
Nantenine, as well as a number of flexible analogs, were evaluated for acetylcholinesterase (AChE) inhibitory activity in microplate spectrophotometric assays based on Ellman's method. It was found that the rigid aporphine core of nantenine is an important structural requirement for its anticholinesterase activity. Nantenine showed mixed inhibition kinetics in enzyme assays. Molecular docking experiments suggest that nantenine binds preferentially to the catalytic site of AChE but is also capable of interacting with the peripheral anionic site (PAS) of the enzyme, thus accounting for its mixed inhibition profile. The aporphine core of nantenine may thus be a useful template for the design of novel PAS or dual-site AChE inhibitors. Inhibiting the PAS is desirable for prevention of aggregation of the amyloid peptide Aβ, a major causative factor in the progression of Alzheimer's disease (AD).
南天宁及其一些柔性类似物,根据 Ellman 法在微孔板分光光度测定法中,被评估为乙酰胆碱酯酶 (AChE) 的抑制活性。研究发现,南天宁刚性的阿朴啡核是其抗胆碱酯酶活性的重要结构要求。南天宁在酶测定中表现出混合抑制动力学。分子对接实验表明,南天宁可优先与 AChE 的催化位点结合,但也能够与酶的外周阴离子位点 (PAS) 相互作用,从而解释了其混合抑制特性。因此,南天宁的阿朴啡核可能是设计新型 PAS 或双位点 AChE 抑制剂的有用模板。抑制 PAS 对于防止淀粉样肽 Aβ的聚集是可取的,Aβ是阿尔茨海默病 (AD) 进展的主要致病因素。