2. Academic Validation
  3. Cannabitwinol, a Dimeric Phytocannabinoid from Hemp, Cannabis sativa L., Is a Selective Thermo-TRP Modulator

Cannabitwinol, a Dimeric Phytocannabinoid from Hemp, Cannabis sativa L., Is a Selective Thermo-TRP Modulator

  • J Nat Prod. 2020 Sep 25;83(9):2727-2736. doi: 10.1021/acs.jnatprod.0c00668.
Giuseppina Chianese 1,  Annalisa Lopatriello 1,  Aniello Schiano-Moriello 2 3,  Diego Caprioglio 4,  Daiana Mattoteia 4,  Emanuele Benetti 5,  Daniele Ciceri 5,  Lolita Arnoldi 5,  Eric De Combarieu 5,  Rosa M Vitale 6,  Pietro Amodeo 6,  Giovanni Appendino 4,  Luciano De Petrocellis 2,  Orazio Taglialatela-Scafati 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
  • 2 Endocannabinoid Research Group (ERG)-Institute of Biomolecular Chemistry (ICB)-National Research Council (CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
  • 3 Epitech Group SpA, Saccolongo, 35030 Padova, Italy.
  • 4 Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy.
  • 5 INDENA SpA, Via Don Minzoni 6, Settala, 20090 Milan, Italy.
  • 6 Institute of Biomolecular Chemistry (ICB)-National Research Council (CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
PMID: 32880179 DOI: 10.1021/acs.jnatprod.0c00668
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 1H NMR signals and lack of expected 2D NMR correlations at room temperature, was fully carried out in methanol-d4 at -30 °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.

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