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

Authors Nyman E, Franzén B, Nolting A, Klement G, Liu G, Nilsson M, Rosén A, Björk C, Weigelt D, Wollberg P, Karila P, Raboisson P

Received 31 August 2012

Accepted for publication 3 October 2012

Published 30 January 2013 Volume 2013:6 Pages 59—70


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

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 Raboisson1

1Neuroscience, Innovative Medicines CNS/Pain, AstraZeneca R&D, Södertälje, Sweden; 2Division of Oral and Maxillofacial Surgery, Karolinska Institute/Karolinska University Hospital, Huddinge, Sweden; 3Clinical TA NS Early Development, 4Medicinal Chemistry, Innovative Medicines CNS/Pain, AstraZeneca R&D, Södertälje, Sweden

*These authors contributed equally to this work

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.

Keywords: pain, pharmacology, antagonist, chimeric proteins, dental pulp, inflammation, neuropeptide, calcitonin gene-related peptide, CGRP

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