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A high-throughput electrophysiology assay identifies inhibitors of the inwardly rectifying potassium channel Kir7.1
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Wright, P. D., Kanumilli , S., Tickle, David, Cartland, J., Bouloc, N., Dale, T., Tresize, D. J., McCloskey, Conor, McCavera, Samantha, Blanks, Andrew M., Kettleborough, Catherine and Jerman, Jeff (2015) A high-throughput electrophysiology assay identifies inhibitors of the inwardly rectifying potassium channel Kir7.1. Journal of Biomolecular Screening, Volume 20 (Number 6). pp. 739-747. doi:10.1177/1087057115569156 ISSN 1087-0571.
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Official URL: http://dx.doi.org/10.1177/1087057115569156
Abstract
Kir7.1 is an inwardly rectifying potassium channel that has been implicated in controlling the resting membrane potential of the myometrium. Abnormal uterine activity in pregnancy plays an important role in postpartum hemorrhage, and novel therapies for this condition may lie in manipulation of membrane potential. This work presents an assay development and screening strategy for identifying novel inhibitors of Kir7.1. A cell-based automated patch-clamp electrophysiology assay was developed using the IonWorks Quattro (Molecular Devices, Sunnyvale, CA) system, and the iterative optimization is described. In total, 7087 compounds were tested, with a hit rate (>40% inhibition) of 3.09%. During screening, average Z' values of 0.63 ± 0.09 were observed. After chemistry triage, lead compounds were resynthesized and activity confirmed by IC50 determinations. The most potent compound identified (MRT00200769) gave rise to an IC50 of 1.3 µM at Kir7.1. Compounds were assessed for selectivity using the inwardly rectifying potassium channel Kir1.1 (ROMK) and hERG (human Ether-à-go-go Related Gene). Pharmacological characterization of known Kir7.1 inhibitors was also carried out and analogues of VU590 tested to assess selectivity at Kir7.1.
Item Type: | Journal Article | ||||||||
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Subjects: | R Medicine > RM Therapeutics. Pharmacology T Technology > T Technology (General) |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Ion channels, Pharmacology, Potassium channels, Medical screening | ||||||||
Journal or Publication Title: | Journal of Biomolecular Screening | ||||||||
Publisher: | Sage Publications, Inc. | ||||||||
ISSN: | 1087-0571 | ||||||||
Official Date: | 5 February 2015 | ||||||||
Dates: |
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Volume: | Volume 20 | ||||||||
Number: | Number 6 | ||||||||
Page Range: | pp. 739-747 | ||||||||
DOI: | 10.1177/1087057115569156 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Restricted or Subscription Access |
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