SCRAs with a “Brand” New Look: In Vitro Cannabinoid Activity Profiling of Generic Ban-Evading Brominated Synthetic Cannabinoid Receptor Agonists and their Analogs

Since the enactment of the Chinese generic ban (2021), the synthetic cannabinoid receptor agonist (SCRA) market has vastly changed and now encompasses unexpected, ban-evading structures such as brominated and tail-less compounds. Six new SCRAs were functionally characterized at CB1 and CB2 using 2 distinct activity-based assays, monitoring βarr2 recruitment (NanoBiT® assay) and Ca2+ mobilization (AequoScreen® assay). Brominated, tailed SCRAs (ADB-5’Br-BUTINACA, MDMB-5’Br-BUTINACA) showed high efficacy and potency at CB1. Interestingly, switching the bromine for a fluorine (ADB-5’F-BUTINACA) resulted in an even more pronounced CB activity. Tail-less, brominated compounds (ADB-5’Br-INACA, MDMB-5’Br-INACA) retained activity at both receptors, albeit with decreased potency compared to their tailed counterparts, which was confirmed in both assays. Removing the bromine group from the tail-less core resulted in decreased activity (ADB-INACA), evidencing the positive effect of bromine substitution. This study provides essential information for both drug law enforcement agencies and health care workers, as it can be expected that the ever-lasting cat-and-mouse game that describes the SCRA market will carry on, with the surge of new and unexpected substances remaining a great challenge for several fields.