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Synthesis 2024; 56(05): 809-820
DOI: 10.1055/s-0042-1751539
paper

Synthesis of Stilbenyl and Bibenzyl Cannabinoids and Analysis of Their Cannabimimetic Potential

Erin Noel Jordan 
a   Technical Biochemistry Laboratory, Faculty of Biochemical and Chemical Engineering, Technical University Dortmund University, 44227 Dortmund, Germany
,
Gia-Nam Nguyen 
a   Technical Biochemistry Laboratory, Faculty of Biochemical and Chemical Engineering, Technical University Dortmund University, 44227 Dortmund, Germany
c   MINDbioscience GmbH, Emil-Figge-Strasse 76a, 44227 Dortmund, Germany
,
Inés Reynoso-Moreno
b   Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland
,
Jürg Gertsch 
b   Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland
,
Oliver Kayser  ∗
a   Technical Biochemistry Laboratory, Faculty of Biochemical and Chemical Engineering, Technical University Dortmund University, 44227 Dortmund, Germany
› Author AffiliationsWe acknowledge financial support from the Bundesministerium für Bildung und Forschung (German Federal Ministry of Education and Research) in the program VIPplus for the project CannaCell (03VP06370).
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Abstract

Efficient syntheses of stilbenyl and bibenzyl cannabinoids were investigated. A comprehensive synthetic strategy without protecting groups was constructed on direct C–C condensation and [3+3] annulation followed by different intramolecular cyclizations or reductive aromatization. In total, 14 cannabinoids representing chemical diversity were tested for their effect on cannabinoid receptors CB1 and CB2, and their inhibitory activity on fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in vitro. Interestingly, different bibenzyl cannabinoids showed moderately potent nanomolar activity. One exception was a stilbenyl cannabichromene, which was characterized as a substance that may have psychoactive properties. Only a bibenzyl cannabidiol showed a significant inhibition of FAAH. The structure–activity relationships of the synthesized cannabinoids are discussed. Our data show the versatility of the cannabinoid scaffold to generate nature-inspired cannabimimetics.

Key words

cannabinoid synthesis - bibenzyl cannabinoids - stilbenyl cannabinoids - CB receptors - receptor pharmacology

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0042-1751539.
  • Supporting Information


Publication History

Received: 16 September 2023

Accepted after revision: 21 November 2023

Article published online:
11 January 2024

© 2024. Thieme. All rights reserved

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