Targeting TRPA1 with Novel Synthetic Compounds Based on Different Scaffolds to Reduce Acute and Chronic Pain

The transient receptor potential ankyrin 1 (TRPA1) channel is a nonselective cation channel that detects noxious stimuli. Due to its role in acute and chronic pain transmission, interest in this receptor as a potential therapeutic target has grown. Among the natural compounds tested, δ-sanshool proved to be a promising modulator of TRPA1 due to its interaction with specific receptor cysteines. Starting from this polyunsaturated amide, we designed and prepared a small library of derivatives in which different amide heads were introduced and the length of the unsaturated chain was changed. The newly synthesized compounds were tested in vitro, and the results were rationalized by a molecular docking approach. Two of them, characterized by an agonist profile, were evaluated in vivo in the formalin-induced nociceptive response test, exhibiting promising analgesic properties.