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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.


Arundhasa Chandrabalan

Martin J. McPhillie


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 desensitising effects, and CADs with electron-donating groups were either partial agonists or antagonists. Site-directed mutagenesis revealed that the CADs do not undergo conjugate addition reaction with TRPA1, and 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.


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.

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
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 170
Pages 141-156
Keywords Transient receptor potential ankyrin 1; TRPA1; TRP; N-Cinnamoylanthranilic acid; Tranilast; Calcium signaling; Binding site; Non-covalent
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