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dc.contributor.authorBeswick, Paul
dc.contributor.authorWahab, Ben
dc.contributor.authorHoney, Mark A.
dc.contributor.authorParadowski, Michael
dc.contributor.authorJiang, Ke
dc.contributor.authorLochner, Martin
dc.contributor.authorMurrell-Lagnado, Ruth D.
dc.contributor.authorThompson, Andrew J.
dc.date.accessioned2019-07-03T09:19:54Z
dc.date.available2019-07-03T09:19:54Z
dc.date.issued2019-06-24
dc.identifier.citationBeswick, P., Wahab, B., Honey, M. A., Paradowski, M., Jiang, K., Lochner⁠, M., Murrell-Lagnado, R. D. and Thompson, A. J. (2019) A challenge finding P2X1 and P2X4 ligands, Neuropharmacology, 157 (October 2019), DOI: 10.1016/j.neuropharm.2019.107674en
dc.identifier.issn0028-3908en
dc.identifier.doi10.1016/j.neuropharm.2019.107674en
dc.identifier.urihttp://hdl.handle.net/2436/622514
dc.description.abstractIdentifying novel small-molecule P2X1 and P2X4 ligands with sub-type specificity and high-affinity remains a pharmacological challenge. Here we use computational methods, electrophysiology and fluorescent microplate assays to screen for ligand candidates acting at these receptors. Modelling and docking identified 80 compounds for testing at P2X4 receptors, and 20 of these showed >50% inhibition in fluorescence-based assays, making them appealing for further SAR studies. Confirmation of activity by two-electrode voltage clamp, followed by their elaboration resulted in only minor improvements in potency, with the highest IC50 being 295 μM. Testing on P2X1 receptors, resulted in a series of biguanide compounds that yielded a maximum IC50 of 100 μM, but no consistent SAR could be found. Potencies of established antagonists gave expected results, although the measured potencies varied between techniques and no antagonism could be found for compounds such as paroxetine, carbamazepine, 9(10H)-acridanone, acridinol and phenoxazine-type heterocycles. This study highlights the challenge of identifying P2X4 and P2X1 ligands and suggests that a combination of complimentary approaches is needed if we are to be confident of ligand activities at these receptors.en
dc.description.sponsorshipThe British Heart Foundation supported AJT (grant; PG/13/39/30293). RML was supported by EU COST Action BM1046.en
dc.formatapplication/PDFen
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttps://www.sciencedirect.com/science/article/pii/S0028390819302345en
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subjectantagonisten
dc.subjectagonisten
dc.subjectP2X1en
dc.subjectP2X4en
dc.subjectliganden
dc.subjectscreenen
dc.subjection channelen
dc.subjectfunctionen
dc.subjecttwo-electrode voltage clampen
dc.subjectmicroplateen
dc.titleA challenge finding P2X1 and P2X4 ligandsen
dc.typeJournal articleen
dc.identifier.journalNeuropharmacologyen
dc.date.accepted2019-06-17
rioxxterms.funderUniversity of Wolverhamptonen
rioxxterms.identifier.projectPG/13/39/30293en
rioxxterms.identifier.projectBM1046en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
rioxxterms.licenseref.startdate2020-06-24en
refterms.dateFCD2019-07-03T09:19:08Z
refterms.versionFCDAM


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