Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands

  • Bioorg Med Chem Lett. 2015 Mar 1;25(5):1009-11. doi: 10.1016/j.bmcl.2015.01.039.
Danilo Del Prete  1 ,  Diego Caprioglio  1 ,  Giovanni Appendino  1 ,  Alberto Minassi  2 ,  Aniello Schiano-Moriello  3 ,  Vincenzo Di Marzo  3 ,  Luciano De Petrocellis  4
Affiliations
  • 1. Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
  • 2. Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy. Electronic address: [email protected].
  • 3. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
  • 4. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy. Electronic address: [email protected].
PMID: 25666822 DOI: 10.1016/j.bmcl.2015.01.039
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.

Keywords
Capsaicin; Rinvanil; Structure–activity relationships; TRPA1; TRPV1.