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

vitro pharmacological characterization of a novel TRPA1 antagonist and proof of mechanism in a human dental pulp model Original Research (926) Total Article Views Authors: Nyman E, Franzén B, Nolting A, Klement G, Liu G, Nilsson M, Rosén A, Bj rk C, Weigelt D, Wollberg P, Karila P, Raboisson P Published Date January 2013 Volume 2013:6 Pages 59 - 70 DOI: http://dx.doi.org/10.2147/JPR.S37567 Received: 31 August 2012 Accepted: 03 October 2012 Published: 30 January 2013 Eva Nyman,1,* Bo Franzén,1,* Andreas Nolting,1 G ran Klement,1 Gang Liu,1 Maria Nilsson,1 Annika Rosén,2 Charlotta Bj rk,3 Dirk Weigelt,4 Patrik Wollberg,1 Paul Karila,1 Patrick Raboisson1 1Neuroscience, Innovative Medicines CNS/Pain, AstraZeneca R&D, S dert lje, 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, S dert lje, 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.