title: 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.
authors: Neuroscience, Innovative Medicines CNS/Pain, AstraZeneca R&D, Södertälje, Sweden.
authors: Eva
authors: E
authors: Nyman
authors: Bo
authors: B
authors: Franzén
authors: Andreas
authors: A
authors: Nolting
authors: Göran
authors: G
authors: Klement
authors: Gang
authors: G
authors: Liu
authors: Maria
authors: M
authors: Nilsson
authors: Annika
authors: A
authors: Rosén
authors: Charlotta
authors: C
authors: Björk
authors: Dirk
authors: D
authors: Weigelt
authors: Patrik
authors: P
authors: Wollberg
authors: Paul
authors: P
authors: Karila
authors: Patrick
authors: P
authors: Raboisson
keywords: CGRP; antagonist; calcitonin gene-related peptide; chimeric proteins; dental pulp; inflammation; neuropeptide; pain; pharmacology
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