Leucettamols, Bifunctionalized Marine Sphingoids, Act as Modulators of TRPA1 and TRPM8 Channels

Leucettamols, bifunctionalized sphingoid-like compounds obtained from a marine sponge Leucetta sp., act as non-electrophilic activators of the TRPA1 channel and potent inhibitors of the icilin-mediated activation of the TRPM8 channel, while they are inactive on CB1, CB2 and TRPV1 receptors. Leucettamols represent the first compounds of marine origin to target TRPA1 and the first class of natural products to inhibit TRPM8 channels. The preparation of a small series of semi-synthetic derivatives revealed interesting details on the structure-activity relationships within this new chemotype of simple acyclic TRP modulators.