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In vitro pharmacological characterization of a novel TRPA1 antagonist and proof of mechanism in a human dental pulp model.


ABSTRACT: 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.

SUBMITTER: Nyman E 

PROVIDER: S-EPMC3565573 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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In vitro pharmacological characterization of a novel TRPA1 antagonist and proof of mechanism in a human dental pulp model.

Nyman Eva E   Franzén Bo B   Nolting Andreas A   Klement Göran G   Liu Gang G   Nilsson Maria M   Rosén Annika A   Björk Charlotta C   Weigelt Dirk D   Wollberg Patrik P   Karila Paul P   Raboisson Patrick P  

Journal of pain research 20130130


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. Fi  ...[more]

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