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.

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 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.

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
• Electronic ISSN: 1768-3254
• 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