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Discovery of Non-Electrophilic Capsaicinoid-Type TRPA1 Ligands

Discovery of Non-Electrophilic Capsaicinoid-Type TRPA1 Ligands

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

Bioorg Med Chem Lett. 2015 Mar 1;25(5):1009-11.

PMID: 25666822

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP457643606	Rinvanil		457643-60-6	Price

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