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.
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.
Gijsen
Harrie J M
HJ
Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium. hgijsen@its.jnj.com
Berthelot
Didier
D
Zaja
Mirko
M
Brône
Bert
B
Geuens
Ivo
I
Mercken
Marc
M
D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D002460:Cell Line; D003984:Dibenzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003989:Dibenzoxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005470:Fluorometry; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists*; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D013665:Tear Gases / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000819:agonists*
C553283:5H-dibenzo(b,e)azepine-10-carboxylic acid methyl ester; D015220:Calcium Channels; D003984:Dibenzazepines; D003989:Dibenzoxazepines; D008024:Ligands; D009419:Nerve Tissue Proteins; D010077:Oxazepines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D013665:Tear Gases; D050051:Transient Receptor Potential Channels; C553284:dibenzo(b,f)(1,4)oxazepine-4-carboxylic acid methyl ester; D002118:Calcium