2. Academic Validation
  3. N-Cinnamoylanthranilates as human TRPA1 modulators: Structure-activity relationships and channel binding sites

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

  • Eur J Med Chem. 2019 May 15;170:141-156. doi: 10.1016/j.ejmech.2019.02.074.
Arundhasa Chandrabalan 1,  Martin J McPhillie 2,  Alyn H Morice 3,  Andrew N Boa 4,  Laura R Sadofsky 5
Affiliations

Affiliations

  • 1 Department of Chemistry & Biochemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK; Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
  • 2 School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
  • 3 Respiratory Medicine, Hull York Medical School, Castle Hill Hospital, Cottingham, HU16 5JQ, UK.
  • 4 Department of Chemistry & Biochemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. Electronic address: A.N.Boa@hull.ac.uk.
  • 5 Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Cottingham Road, Hull, HU6 7RX, UK. Electronic address: Laura.Sadofsky@hyms.ac.uk.
PMID: 30878828 DOI: 10.1016/j.ejmech.2019.02.074
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.

Keywords

Binding site; Calcium signaling; N-Cinnamoylanthranilic acid; Non-covalent; TRP; TRPA1; Tranilast; Transient receptor potential ankyrin 1.

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