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

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.