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Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands
- Source :
- Bioorganic & medicinal chemistry letters, 25 (2015): 1009–1011. doi:10.1016/j.bmcl.2015.01.039, info:cnr-pdr/source/autori:Del Prete, Danilo; Caprioglio, Diego; Appendino, Giovanni; Minassi, Alberto; Schiano-Moriello, Aniello; Di Marzo, Vincenzo; De Petrocellis, Luciano/titolo:Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands/doi:10.1016%2Fj.bmcl.2015.01.039/rivista:Bioorganic & medicinal chemistry letters (Print)/anno:2015/pagina_da:1009/pagina_a:1011/intervallo_pagine:1009–1011/volume:25
- Publication Year :
- 2014
-
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. (C) 2015 Elsevier Ltd. All rights reserved.
- Subjects :
- Agonist
medicine.drug_class
Stereochemistry
Nonivamide
Clinical Biochemistry
TRPV1
Pharmaceutical Science
Capsaicinoid
TRPV Cation Channels
Tetrazoles
Structure-activity relationships
Nerve Tissue Proteins
Ligands
Biochemistry
TRPA1
Vanilloids
chemistry.chemical_compound
Structure-Activity Relationship
Transient Receptor Potential Channels
Drug Discovery
medicine
Moiety
Humans
Tetrazole
Rinvanil
Molecular Biology
TRPA1 Cation Channel
Organic Chemistry
food and beverages
HEK293 Cells
chemistry
Sensory System Agents
Molecular Medicine
lipids (amino acids, peptides, and proteins)
Calcium Channels
Pharmacophore
Capsaicin
psychological phenomena and processes
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 25
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....6abdbae4f28df8975958025423348050