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Analogues of morphanthridine and the tear gas dibenz[b,f][1,4]oxazepine (CR) as extremely potent activators of the human transient receptor potential ankyrin 1 (TRPA1) channel.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Oct 14; Vol. 53 (19), pp. 7011-20. - Publication Year :
- 2010
-
Abstract
- The TRPA1 channel can be considered as a key biological sensor to irritant chemicals. In this paper, the discovery of 11H-dibenz[b,e]azepines (morphanthridines) and dibenz[b,f][1,4]oxazepines is described as extremely potent agonists of the TRPA1 receptor. This has led to the discovery that most of the known tear gases are potent TRPA1 activators. The synthesis and biological activity of a number of substituted morphanthridines and dibenz[b,f][1,4]oxazepines have given insight into the SAR around this class of TRPA1 agonists, with EC(50) values ranging from 1 μM to 0.1 nM. Compounds 6 and 32 can be considered as the most potent TRPA1 agonists known to date, with 6 now being used successfully as a screening tool in the discovery of TRPA1 antagonists. The use of ligands such as 6 and 32 as pharmacological tools may contribute to the basic knowledge of the TRPA1 channel and advance the development of TRPA1 antagonists as potential treatment for conditions involving TRPA1 activation, including asthma and pain.
- Subjects :
- Calcium metabolism
Calcium Channels
Cell Line
Dibenzazepines chemistry
Dibenzazepines pharmacology
Dibenzoxazepines chemistry
Dibenzoxazepines pharmacology
Fluorometry
Humans
Intracellular Space metabolism
Ligands
Membrane Potentials drug effects
Oxazepines chemistry
Oxazepines pharmacology
Patch-Clamp Techniques
Structure-Activity Relationship
TRPA1 Cation Channel
Tear Gases chemistry
Tear Gases pharmacology
Dibenzazepines chemical synthesis
Dibenzoxazepines chemical synthesis
Nerve Tissue Proteins agonists
Oxazepines chemical synthesis
Tear Gases chemical synthesis
Transient Receptor Potential Channels agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20806939
- Full Text :
- https://doi.org/10.1021/jm100477n