Eva Nyman 1 , Bo Franzén 1 , Andreas Nolting 1 , Göran Klement 1 , Gang Liu 1 , Maria Nilsson 1 , Annika Rosén 2 , Charlotta Björk 3 , Dirk Weigelt 4 , Patrik Wollberg 1 , Paul Karila 1 , Patrick Raboisson 1
30 January 2013
AZ465 is a novel selective transient receptor potential cation channel, member A1 (TRPA1) antagonist identified during a focused drug discovery effort. In vitro, AZ465 fully inhibits activation by zinc, O-chlorobenzylidene malononitrile (CS), or cinnamaldehyde of the human TRPA1 channel heterologously expressed in human embryonic kidney cells. Our data using patch-clamp recordings and mouse/human TRPA1 chimeras suggest that AZ465 binds reversibly in the pore region of the human TRPA1 channel. Finally, in an ex vivo model measuring TRPA1 agonist-stimulated release of neuropeptides from human dental pulp biopsies, AZD465 was able to block 50%–60% of CS-induced calcitonin gene-related peptide release, confirming that AZ465 inhibits the native human TRPA1 channel in neuronal tissue.