TRPA1 modulators in preclinical development

Abstract

Background: Transient receptor potential ankyrin 1 (TRPA1) has been revealed as a pivotal molecular entity in sensory biology, especially as a sensor of chemical irritants present in foods, atmospheric pollutants and neurotoxic compounds. In addition, this channel appears responsible for detecting physical signals such as noxious cold and mechanical forces. Objectives: There is mounting evidence that TRPA1 is involved in the pathophysiology of several diseases, and directly contributes to the cold and mechanical hyperalgesia present in inflammatory and neuropathic states. Therefore, TRPA1 is an important therapeutic target for drug development. Intriguingly, however, the number of receptor antagonists reported thus far is notably low, as compared with the large number of receptor agonists. Nonetheless, known TRPA1 antagonists display very promising in vivo activity against mechanical hypersensitivity and cold hyperalgesia, although at therapeutic doses that are still high for drug development. A significant effort is being pursued using medicinal chemistry programs to modify the initial scaffolds for evolving lead compounds for preclinical and clinical assays. Conclusion: It is anticipated that this field will blossom in the near future, and the number and therapeutic indexes of new antagonists will be significantly improved. Furthermore, it will not be surprising if TRPA1 agonists also have some therapeutic potential, akin to capsaicin.