PubMed 25666822

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: TRP , TRPA , TRPA1 , TRPV , TRPV1

Title: Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands.

Authors: Danilo Del Prete, Diego Caprioglio, Giovanni Appendino, Alberto Minassi, Aniello Schiano-Moriello, Vincenzo Di Marzo, Luciano De Petrocellis

Journal, date & volume: Bioorg. Med. Chem. Lett., 2015 Mar 1 , 25, 1009-11

PubMed link:

Replacement of the benzylamide motif of synthetic capsaicin (nonivamide, 1c) with a tetrazole moiety was detrimental for TRPV1 binding, but unexpectedly generated a potent and non-electrophilic TRPA1 agonist (4a). Spurred by this observation and by the relatively small number of non-covalent TRPA1 ligands reported so far, the benzylamide-to-tetrazole swap was investigated in the more lipophilic and powerful vanilloids olvanil (1d), rinvanil (1e), and phenylacetylrinvanil (1f). In all cases, the replacement was detrimental for TRPV1 binding, but a clear modulation of TRPA1 activity was observed. These observations show that the capsaicinoid pharmacophore displays orthogonal structure-activity relationships for TRPV1 and TRPA1 binding, and suggest the possibility of obtaining compounds with dual TRPV1/TRPA1 modulatory properties by exploration of the chemical space around the capsaicin motif.