Skip to main content

Research Repository

Advanced Search

N-cinnamoylanthranilates as human TRPA1 modulators: Structure-activity relationships and channel binding sites

Chandrabalan, Arundhasa; McPhillie, Martin J.; Morice, Alyn H.; Boa, Andrew N.; Sadofsky, Laura R.

Authors

Arundhasa Chandrabalan

Martin J. McPhillie

Alyn H. Morice

Dr Laura Sadofsky L.R.Sadofsky@hull.ac.uk
Lecturer in Respiratory Medicine/ Academic lead for postgraduate training in HYMS



Abstract

The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel, which detects noxious stimuli leading to pain, itch and cough. However, the mechanism(s) of channel modulation by many of the known, non-reactive modulators has not been fully elucidated. N-cinnamoylanthranilic acid derivatives (CADs) contain structural elements from the TRPA1 modulators cinnamaldehyde and flufenamic acid, so it was hypothesized that specific modulators could be found amongst them and more could be learnt about modulation of TRPA1 with these compounds. A series of CADs was therefore screened for agonism and antagonism in HEK293 cells stably transfected with WT-human (h)TRPA1, or C621A, F909A or F944A mutant hTRPA1. Derivatives with electron-withdrawing and/or electron-donating substituents were found to possess different activities. CADs with inductive electron-withdrawing groups were agonists with desensitizing effects, and CADs with electron-donating groups were either partial agonists or antagonists. Site-directed mutagenesis revealed the CADs do not undergo conjugate addition reaction with TRPA1 and reveal that F944 is a key residue involved in the non-covalent modulation of TRPA1 by CADs, as well as many other structurally distinct non-reactive TRPA1 ligands already reported.

Citation

Chandrabalan, A., McPhillie, M. J., Morice, A. H., Boa, A. N., & Sadofsky, L. R. (2019). N-cinnamoylanthranilates as human TRPA1 modulators: Structure-activity relationships and channel binding sites. European Journal of Medicinal Chemistry, 170, 141-156. https://doi.org/10.1016/j.ejmech.2019.02.074

Journal Article Type Article
Acceptance Date Feb 27, 2019
Online Publication Date Mar 4, 2019
Publication Date May 15, 2019
Deposit Date Mar 4, 2019
Publicly Available Date Mar 5, 2020
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 170
Pages 141-156
DOI https://doi.org/10.1016/j.ejmech.2019.02.074
Keywords Transient receptor potential ankyrin 1; TRPA1; TRP; N-Cinnamoylanthranilic acid; Tranilast; Calcium signaling; Binding site; Non-covalent
Public URL https://hull-repository.worktribe.com/output/1354332
Publisher URL https://www.sciencedirect.com/science/article/pii/S0223523419302065?via%3Dihub

Files

Article (2 Mb)
PDF

Publisher Licence URL
https://creativecommons.org/licenses/by-nc-nd/4.0/

Copyright Statement
© 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/





You might also like



Downloadable Citations