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A challenge finding P2X1 and P2X4 ligands

A challenge finding P2X1 and P2X4 ligands

Beswick, Paul, Wahab, Ben, Honey, Mark A. ORCID: 0000-0001-7272-476X, Paradowski, Michael, Jiang, Ke, Lochner, Martin, Murrell-Lagnado, Ruth D. and Thompson, Andrew J. (2019) A challenge finding P2X1 and P2X4 ligands. Neuropharmacology, 157:107674. ISSN 0028-3908 (doi:

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Identifying novel small-molecule P2X1 and P2X4 ligands with sub-type specificity and high-affinity remains apharmacological challenge. Here we use computational methods, electrophysiology andfluorescent microplateassays to screen for ligand candidates acting at these receptors. Modelling and docking identified 80 compoundsfor testing at P2X4 receptors, and 20 of these showed > 50% inhibition influorescence-based assays, makingthem appealing for further SAR studies. Confirmation of activity by two-electrode voltage clamp, followed bytheir elaboration resulted in only minor improvements in potency, with the highestIC50being 295μM. Testingon P2X1 receptors, resulted in a series of biguanide compounds that yielded a maximumIC50of 100μM, but noconsistent SAR could be found. Potencies of established antagonists gave expected results, although the mea-sured potencies varied between techniques and no antagonism could be found for compounds such as parox-etine, carbamazepine, 9(10H)-acridanone, acridinol and phenoxazine-type heterocycles. This study highlightsthe challenge of identifying P2X4 and P2X1 ligands and suggests that a combination of complimentary ap-proaches is needed if we are to be confident of ligand activities at these receptors.

Item Type: Article
Uncontrolled Keywords: antagonist, agonist, P2X1, P2X4, ligand, screen, ion channel, function, two-electrode voltage clamp, microplate
Subjects: Q Science > Q Science (General)
Faculty / School / Research Centre / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > School of Science (SCI)
Last Modified: 18 Aug 2020 10:39

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