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

Abstract

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.

Development of A New Delivery System Based on Drug-Loadable Electrospun Nanofibers for Psoriasis Treatment

“…Since the TRPV1 channel allows the non-selective passage of cations such as Ca 2+ when activated, a Ca 2+ fluorescence probe has been used to indirectly quantify such activation, which might be induced by the experimental treatments. Thus, Ca 2+ fluorography assays were performed by using the probe Fluo-4 NW (Molecular Probes-Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 2.5 mM of probenecid, which improves the permeation of the probe in the cells and inhibits losses of fluorescence by avoiding its exit to the cellular exterior, as was recently reported by Serafini et al (2018) [37].…”

Inflammatory mediators causing cutaneous chronic itch in some diseases via transient receptor potential channel subfamily V member 1 and subfamily A member 1

“…However, the treatment of chronic itch has always been a big problem. A number of TRPV1 antagonists have been developed 53 and some TRPV1 channel inhibitors also trialed at the clinical stage. 52 We could pay more attention to the methods of curing chronic itch.…”

“…10,11 The monoclonal antibodies of IL-31, IL-4, IL-13 and TSLP are being clinically researched. A number of TRPV1 antagonists have been developed 53 and some TRPV1 channel inhibitors also trialed at the clinical stage. 3,4,54 Until now, at least 15 small molecular compounds have entered phase 1 clinical trials and five of these antagonists have progressed to phase II clinical trials.…”

Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

“…In 2014, imidazothiazole compounds were reported by Tojo et al as potent IDO1 inhibitors, with the reference compound 1 (Figure 1) displaying an IC 50 value of 1.9 µM (rhIDO1) [10]. Taking advantage of our extensive experience both in multicomponent reactions [11,12] and click chemistry approach [13], as well as their exploitation in drug discovery [14,15,16,17], we decided to synthesize in parallel two series of imidazothiazole analogues.…”