Analogues of Morphanthridine and the Tear Gas Dibenz[b,f][1,4]oxazepine (CR) as Extremely Potent Activators of the Human Transient Receptor Potential Ankyrin1 (TRPA1) Channel

The TRPA1 channel can be considered as a key biological sensor to irritant chemicals. In this paper. the discovery of H/1-dibenz[b,e]azepines (morphanthridines) and dibenz[b,f][1,4]oxazepines is described as extremely potent agonists oft he 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]oxfizepines have given insight into the SA R around this class or TRPA1 agonists, with EC(50) values ranging from 1 mu M 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;, 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.