Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders

Despite being an
old molecule, capsaicin is still a hot topic in the scientific community,
and the development of new capsaicinoids is a promising pharmacological
approach in the management of skin disorders related to inflammation
and pruritus. Here we report the synthesis and the evaluation of capsaicin
soft drugs that undergo deactivation by the hydrolyzing activity of
skin esterases. The implanting of an ester group in the lipophilic
moiety of capsaicinoids by the Passerini multicomponent reaction affords
both agonists and antagonists that retain transient receptor potential
vanilloid 1 channel (TRPV1) modulating activity and, at the same time,
are susceptible to hydrolysis. The most promising antagonist identified
shows in vivo anti-nociceptive activity on pruritus and hyperalgesia
without producing hyperthermia, thus validating it as novel treatment
for dermatological conditions that implicate TRPV1 channel dysfunction.