2. Academic Validation
  3. Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands

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

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: alberto.minassi@pharm.unipmn.it.
  • 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: luciano.depetrocellis@icb.cnr.it.
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.

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