Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization

Transient receptor potential ankyrin
1 (TRPA1) channel, as a nonselective
ligand-gated cation channel robustly in dorsal root ganglion sensory
neurons, is implicated in sensing noxious stimuli and nociceptive
signaling. However, small-molecule tools targeting TRPA1 lack temporal
and spatial resolution, limiting their use for validation of TRPA1
as a therapeutic target for pain. In our previous work, we found that
4,4′-(diazene-1,2-diyl)­dianiline (AB1) is a photoswitchable
TRPA1 agonist, but the poor water solubility and activity hinder its
further development. Here, we report a series of specific and potent
azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2)
that enable optical control of the TRPA1 channel. Two representative
compounds 1g and 2c can alleviate capsaicin-induced
pain in the cheek model of mice through channel desensitization but
not in TRPA1 knockout mice. Taken together, our findings demonstrate
that photoswitchable TRPA1 agonists can be used as pharmacological
tools for study of pain signaling.