Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands.

Authors :: Del Prete D
Caprioglio D
Appendino G
Minassi A
Schiano-Moriello A
Di Marzo V
De Petrocellis L
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Mar 01; Vol. 25 (5), pp. 1009-11. Date of Electronic Publication: 2015 Jan 28.
Publication Year :: 2015
Abstract: 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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)