Parsonage, G, Cuthbertson, K, Endesh, N et al. (16 more authors) (Cover date: August 2023) Improved PIEZO1 agonism through 4-benzoic acid modification of Yoda1. British Journal of Pharmacology, 180 (16). pp. 2039-2063. ISSN 0007-1188
Abstract
Background and Purpose
PIEZO1 forms mechanically activated calcium-permeable non-selective cation channels in numerous species and cell types. Options for pharmacological modulation are limited and so we modified a PIEZO1 small-molecule agonist (Yoda1) to advance capability for modulation.
Experimental Approach
Medicinal chemistry generated Yoda1 analogues that were tested in intracellular calcium and patch-clamp assays on cultured cells exogenously expressing human or mouse PIEZO1 or mouse PIEZO2, physico-chemical assays and wire myography assays on vein from mice in which there was genetic disruption of PIEZO1.
Key Results
A Yoda1 analogue (KC159) containing 4-benzoic acid instead of the pyrazine of Yoda1 and its potassium salt (KC289) have equivalent or improved reliability, efficacy and potency compared to Yoda1 in functional assays. Tested against over-expressed mouse PIEZO1 in calcium assays, potency order is KC289 (150)>KC159 (280)>Yoda1 (600) (EC50s in parentheses, nM). There is selectivity for PIEZO1 over other membrane proteins and the physico-chemical properties are more suited to physiological conditions than those of Yoda1. Vasorelaxant effects occur that are consistent with PIEZO1 agonism. 2-benzoic acid substitution, by contrast, fails to generate a modulator.
Conclusion and Implications
4-Benzoic acid modification of Yoda1 improves PIEZO1 agonism. We suggest naming this new modulator Yoda2. It should be a useful tool compound in physiological assays and facilitate efforts to identify a binding site. Such compounds may have therapeutic potential, for example in diseases linked genetically to PIEZO1 such as lymphatic dysplasia.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an author produced version of an article published in the British Journal of Pharmacology, made available under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation RG/17/11/33042 Wellcome Trust 110044/Z/15/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 Nov 2022 11:54 |
Last Modified: | 24 May 2024 01:28 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1111/bph.15996 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:193137 |
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