Synthesis and Evaluation of New Alkylamides Derived from α-Hydroxysanshool, the Pungent Molecule in Szechuan Pepper

Szechuan pepper is widely used in Asia as a spice for its pleasant pungent and tingling sensations, produced by natural alkylamides called sanshools. alpha-Hydroxysanshool, the main alkylamide found in the pericarp of the fruit, stimulates sensory neurons innervating the mouth by targeting two chemosensitive members of the transient receptor potential (TRP) channels, TRPV1 and TRPA1. As it was previously found that configuration of the unsaturations in the alpha-hydroxysanshool alkyl chain is required for TRPA1 but not TRPV1 selectivity, this study aimed at obtaining more potent and selective TRPA1 agonists using alpha-hydroxysanshool as a starting material. This paper reports the preparation of new alkylamides derived from sanshool and their efficacy in stimulating TRPA1 and TRPV1 receptors. The data provide knowledge of the main sanshool chemical functionalities required for TRIP channel activation, but they also evidence new selective and potent TRPA1 agonists based on alpha-hydroxysanshool.