1. Cannabitwinol, a Dimeric Phytocannabinoid from Hemp, Cannabis sativa L., Is a Selective Thermo-TRP Modulator
- Author
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Daniele Ciceri, Luciano De Petrocellis, Orazio Taglialatela-Scafati, Lolita Arnoldi, Pietro Amodeo, Giuseppina Chianese, Emanuele Benetti, Rosa Maria Vitale, Eric de Combarieu, Aniello Schiano-Moriello, Annalisa Lopatriello, Diego Caprioglio, Daiana Mattoteia, Giovanni Appendino, Chianese, G., Lopatriello, A., Schiano-Moriello, A., Caprioglio, D., Mattoteia, D., Benetti, E., Ciceri, D., Arnoldi, L., De Combarieu, E., Vitale, R. M., Amodeo, P., Appendino, G., De Petrocellis, L., and Taglialatela-Scafati, O.
- Subjects
calcium-influx assay ,Stereochemistry ,Dimer ,Pharmaceutical Science ,Methylene bridge ,Molecular dynamics ,01 natural sciences ,Analytical Chemistry ,Enzyme catalysis ,natural compound ,Transient receptor potential channel ,chemistry.chemical_compound ,TRPs ,Drug Discovery ,Pharmacology ,010405 organic chemistry ,Organic Chemistry ,Iminium ,cannabitwinol ,0104 chemical sciences ,phyocannabinoid ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Molecular docking ,Proton NMR ,Molecular Medicine ,Selectivity ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Cannabitwinol (CBDD, 3), the second member of a new class of dimeric phytocannabinoids in which two units are connected by a methylene bridge, was isolated from a hemp (Cannabis sativa L.) industrial extract. The structural characterization of cannabitwinol, complicated by broadening of H-1 NMR signals and lack of expected 2D NMR correlations at room temperature, was fully carried out in methanol-d(4) at -30 degrees C. All the attempts to prepare CBDD by reaction of CBD with formaldehyde or its iminium analogue (Eschenmoser salt) failed, suggesting that this sterically congested dimer is the result of enzymatic reactions on the corresponding monomeric acids. Analysis of the cannabitwinol profile of transient receptor potential (TRP) modulation evidenced the impact of dimerization, revealing a selectivity for channels activated by a decrease of temperature (TRPM8 and TRPA1) and the lack of significant affinity for those activated by an increase of temperature (e.g., TRPV1). The putative binding modes of cannabitwinol with TRPA1 and TRPM8 were investigated in detail by a molecular docking study using the homology models of both channels.
- Published
- 2020