%0 Journal Article
%T In vitro pharmacological characterization of a novel TRPA1 antagonist and proof of mechanism in a human dental pulp model
%A Nyman E
%A Franz&eacute
%A n B
%A Nolting A
%A Klement G
%J Journal of Pain Research
%D 2013
%I Dove Medical Press
%X Eva Nyman,1,* Bo Franz¨Śn,1,* Andreas Nolting,1 G ran Klement,1 Gang Liu,1 Maria Nilsson,1 Annika Ros¨Śn,2 Charlotta Bj rk,3 Dirk Weigelt,4 Patrik Wollberg,1 Paul Karila,1 Patrick Raboisson11Neuroscience, 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 workAbstract: 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%¨C60% 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
%U http://www.dovepress.com/in-vitro-pharmacological-characterization-of-a-novel-trpa1-antagonist--a12103