کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8516348 | 1556575 | 2018 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Identification by virtual screening and functional characterisation of novel positive and negative allosteric modulators of the α7 nicotinic acetylcholine receptor
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کلمات کلیدی
5-HTROCPAM5-hydroxytryptaminenAChRNKCCCDK2AUC - AUCCAII - اسبγ-aminobutyric acid - اسید γ-آمینوبوتیریکcyclin-dependent kinase 2 - سیکلین وابسته به کیناز 2Virtual screening - غربالگری مجازیpositive allosteric modulator - مدولاتور آلوده کننده مثبتAllosteric modulation - مدولاسیون آلوستریکnegative allosteric modulator - منحنی آلوزیستریک منفیarea under the curve - منطقه تحت منحنیNAM - نامreceiver operator characteristic - ویژگی اپراتور گیرندهIon channel - کانال یونیcarbonic anhydrase II - کربنیک آنیدراز IIGABA - گاباnicotinic acetylcholine receptor - گیرنده استیلکولین نیکوتین
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب رفتاری
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Several previous studies have demonstrated that the activity of neurotransmitters acting on ligand-gated ion channels such as the nicotinic acetylcholine receptor (nAChR) can be altered by compounds binding to allosteric modulatory sites. In the case of α7 nAChRs, both positive and negative allosteric modulators (PAMs and NAMs) have been identified and have attracted considerable interest. A recent study, employing revised structural models of the transmembrane domain of the α7 nAChR in closed and open conformations, has provided support for an inter-subunit transmembrane allosteric binding site (Newcombe et al 2017). In the present study, we have performed virtual screening of the DrugBank database using pharmacophore queries that were based on the predicted binding mode of PAMs to α7 nAChR structural models. A total of 81 compounds were identified in the DrugBank database, of which the 25 highest-ranked hits corresponded to one of four previously-identified therapeutic compound groups (carbonic anhydrase inhibitors, cyclin-dependent kinase inhibitors, diuretics targeting the Na+-K+-Cl- cotransporter, and fluoroquinolone antibiotics targeting DNA gyrase). The top-ranked compound from each of these four groups (DB04763, DB08122, furosemide and pefloxacin, respectively) was tested for its effects on human α7 nAChR expressed in Xenopus oocytes using two-electrode voltage-clamp electrophysiology. These studies, conducted with wild-type, mutant and chimeric receptors, resulted in all four compounds exerting allosteric modulatory effects. While DB04763, DB08122 and pefloxacin were antagonists, furosemide potentiated ACh responses. Our findings, supported by docking studies, are consistent with these compounds acting as PAMs and NAMs of the α7 nAChR via interaction with a transmembrane site.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 139, 1 September 2018, Pages 194-204
Journal: Neuropharmacology - Volume 139, 1 September 2018, Pages 194-204
نویسندگان
Charles L.C. Smelt, Victoria R. Sanders, Joseph Newcombe, Richard P. Burt, Tom D. Sheppard, Maya Topf, Neil S. Millar,