کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10593535 981811 2013 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Selective inhibition of human acetylcholinesterase by xanthine derivatives: In vitro inhibition and molecular modeling investigations
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Selective inhibition of human acetylcholinesterase by xanthine derivatives: In vitro inhibition and molecular modeling investigations
چکیده انگلیسی
The commonly used beverage and psychostimulant caffeine is known to inhibit human acetylcholinesterase enzyme. This pharmacological activity of caffeine is partly responsible for its cognition enhancing properties. However, the exact mechanisms of its binding to human cholinesterases (acetyl and butyrylcholinesterase; hAChE and hBuChE) are not well known. In this study, we investigated the cholinesterase inhibition by the xanthine derivatives caffeine, pentoxifylline, and propentofylline. Among them, propentofylline was the most potent AChE inhibitor (hAChE IC50 = 6.40 μM). The hAChE inhibitory potency was of the order: caffeine (hAChE IC50 = 7.25 μM) < pentoxifylline (hAChE IC50 = 6.60 μM) ⩽ propentofylline (hAChE IC50 = 6.40 μM). These compounds were less potent relative to the reference agent donepezil (hAChE IC50 = 0.04 μM). Moreover, they all exhibited selective inhibition of hAChE with no inhibition of hBuChE (IC50 > 50 μM) relative to the reference agent donepezil (hBuChE IC50 = 13.60 μM). Molecular modeling investigations indicate that caffeine binds primarily in the catalytic site (Ser203, Glu334 and His447) region of hAChE whereas pentoxifylline and propentofylline are able to bind to both the catalytic site and peripheral anionic site due to their increased bulk/size, thereby exhibiting superior AChE inhibition relative to caffeine. In contrast, their lack of hBuChE inhibition is due to a larger binding site and lack of key aromatic amino acids. In summary, our study has important implications in the development of novel caffeine derivatives as selective AChE inhibitors with potential application as cognitive enhancers and to treat various forms of dementia.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 15, 1 August 2013, Pages 4336-4341
نویسندگان
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