From nature to drug discovery: Modification of the cannabinoid scaffold and CB receptor interactions

Cannabinoids are important terpenophenolics in Cannabis sativa L. and are found at high concentrations in trichomes. Today, most cannabinoids tested have been isolated from the cannabis plant for their activity on endocannabinoid receptors CB1 and CB2. Unfortunately, most of the rare cannabinoids are not easy accessible why a limited number has been tested so far. In our continued work we have synthetied a series of cannabinoids with varying aliphatic chain lengths (C5, C3, C1, C0). Efficient syntheses of eight key cannabinoids were established and optimized. Predominant cannabinoids like cannabigerol (CBG-C5) and cannabidiol (CBD-C5) were prepared from olivetol via regioselective condensation. Further treatments of CBD led to ∆^9-tetrahydrocannabinol (THC-C5), ∆^8-iso-tetrahydrocannabinol (iso-THC-C5) and cannabinol (CBN-C5). Alternatively, a [3+3] annulation between olivetol and citral yielded the minor cannabinoid cannabichromene (CBC-C5), which was converted into two very rare polycycles cannabicyclol (CBL-C5) and cannabicitran (CBT-C5) in an one-pot reaction (Fig.1). Finally, all eight syntheses were extended by utilizing resorcinol and two phenolic analogs, achieving a cannabinoid group with more than 30 compounds through a facile synthesis strategy. All cannabinoids were tested for recombinant CB1, CB2, FAAS and MAGL activity or inhibition. Based on the different analogs of tested cannabinoids surprising direct and indirect effects were observed for cannabinoids with varying chain lengths. In this talk, we provide a structure-activity-relationship (SAR) and explain the potential interactions of cannabinoids with protein domains of endocannabinoid receptors.