title: Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands.
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.
authors: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
authors: Danilo
authors: D
authors: Del Prete
authors: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
authors: Diego
authors: D
authors: Caprioglio
authors: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
authors: Giovanni
authors: G
authors: Appendino
authors: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy. Electronic address: alberto.minassi@pharm.unipmn.it.
authors: Alberto
authors: A
authors: Minassi
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
authors: Aniello
authors: A
authors: Schiano-Moriello
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy. Electronic address: luciano.depetrocellis@icb.cnr.it.
authors: Luciano
authors: L
authors: De Petrocellis
mesh_terms: D015220:Calcium Channels / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000378:metabolism; D018689:Sensory System Agents / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry* / Q000494:pharmacology*; D050051:Transient Receptor Potential Channels / Q000819:agonists* / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D008024:Ligands; D009419:Nerve Tissue Proteins; D018689:Sensory System Agents; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D013777:Tetrazoles; D050051:Transient Receptor Potential Channels; C054256:olvanil; D002211:Capsaicin; C040937:nonivamide
keywords: Capsaicin; Rinvanil; Structure–activity relationships; TRPA1; TRPV1