In vitro pharmacological characterization of a novel TRPA1 antagonist and proof of mechanism in a human dental pulp model
| Autor: | Paul Karila, Annika Rosén, Patrik Wollberg, Giannoula Klement, Gang Liu, Andreas Nolting, Bo Franzén, Charlotta Björk, Patrick Raboisson, Dirk Weigelt, Eva Nyman, Maria Nilsson |
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| Rok vydání: | 2013 |
| Předmět: |
Neuropeptide
Peptide Calcitonin gene-related peptide Bioinformatics calcitonin gene-related peptide Transient receptor potential channel chimeric proteins Medicine pain CGRP Journal of Pain Research neuropeptide Original Research chemistry.chemical_classification lcsh:R5-920 business.industry Antagonist food and beverages antagonist Fusion protein In vitro Cell biology Anesthesiology and Pain Medicine chemistry inflammation pharmacology dental pulp lcsh:Medicine (General) business psychological phenomena and processes Ex vivo |
| Zdroj: | Journal of Pain Research, Vol 2013, Iss default, Pp 59-70 (2013) Journal of Pain Research |
| ISSN: | 1178-7090 |
| Popis: | 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 Raboisson11Neuroscience, 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 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%–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 |
| Databáze: | OpenAIRE |
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