کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10588014 | 981444 | 2013 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Pharmacological properties and predicted binding mode of arylmethylene quinuclidine-like derivatives at the α3β4 nicotinic acetylcholine receptor (nAChR)
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کلمات کلیدی
root-mean-squared-deviationMECAChBPROCRMSDPDBnAChRACh - آهAcetylcholine - استیل کولینBinding - الزام آورNon-competitive antagonism - انطباق غیر رقابتیProtein Databank - بانک اطلاعاتی پروتئینDocking - داکتCNS - دستگاه عصبی مرکزیStandard Precision - دقت استانداردExtra Precision - دقت فوق العادهcentral nervous system - سیستم عصبی مرکزیenrichment factor - غنی سازی عاملHomology modeling - مدل سازی همگراReceiver operating characteristic curve - منحنی مشخصه عملکرد گیرندهNicotine - نیکوتین Acetylcholine-binding protein - پروتئین اتصال دهنده استیل کولینNIC - چیزیnicotinic acetylcholine receptor - گیرنده استیلکولین نیکوتینNicotinic receptors - گیرنده های نیکوتین
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human α3β4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3β4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC50 values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of α3β4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the α3β4 receptor subtype. Docking into the orthosteric binding site of a α3β4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 5, 1 March 2013, Pages 1450-1455
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 23, Issue 5, 1 March 2013, Pages 1450-1455
نویسندگان
David C. Kombo, Terry A. Hauser, Vladimir P. Grinevich, Matthew S. Melvin, Jon-Paul Strachan, Serguei S. Sidach, Joseph Chewning, Nikolai Fedorov, Kartik Tallapragada, Scott R. Breining, Craig H. Miller,