Pharmacology of generic ban-evading synthetic cannabinoid receptor agonists: are new compounds spicing up the market?
Background: The enactment of the Chinese generic ban on synthetic cannabinoid receptor agonists (SCRAs) in 2021 has caused important changes in the recreational drug landscape. Since then, a large set of compounds with a vast structural diversity and never-seen-before features are continuously being introduced on the market in an effort to bypass the current legislation. This has resulted in a staggering amount of new and, more importantly, unknown substances, available for users who are unaware of their potential harms. Here, we report on the pharmacological investigation of how these structural modifications impact these compounds’ activity at the cannabinoid receptors CB1 and CB2.
Methods: Potency (a measure of the required dose to achieve a certain effect, EC50) and efficacy (the maximum achievable effect, Emax) of an extensive set of newly emerging SCRAs (and potential future analogs) was investigated. To accomplish this, their CB1 and CB2 activation potential was evaluated using in vitro live cell βarr2 recruitment assays, based on functional complementation of a split nanoluciferase enzyme and the measurement of bioluminescence.
Results: The bioassay revealed a wide range of pharmacological activities for new SCRAs. Compounds carrying a ban-evading pyrazole core, such as 5F-3,5-PFUPPYCA, 3,5-ADB-4en-PFUPPYCA and their analogs were essentially inactive at both receptors, despite their recent re-emergence in Scottish prisons. On the other hand, SCRAs with new oxo-indolin cores (e.g. BZO-HEXOXIZID, BZO-POXIZID, BZO-4en-POXIZID) showed an overall moderate potency, with some analogs exhibiting a very pronounced Emax (BZO-CHMOXIZID). Acetamide SCRAs, which bypass the generic ban by carrying an additional methylene function between the core and the linker of the molecule, ranged from being almost inactive (CH-PIATA) to moderately potent at CB1 (ADB-FUBIATA). Stepping away from the conventional head group-core-tail structure for SCRAs, tailless compounds (ADB-INACA, MDMB-5’Br-INACA, ADB-5’Br-INACA) did retain some cannabinoid activity, despite the importance of the tail for the activity being described in literature before. Finally, halogenated SCRAs, carrying a halogen function on the core to evade the generic ban, showed pronounced cannabinoid activity, with a predicted fluorinated analog (ADB-5’F-BUTINACA) being both very potent and very efficacious.
Conclusions: Given the dynamic SCRA market, the continuous pharmacological characterization of newly emerging SCRAs provides valuable and essential information to inform both drug law enforcement agencies and healthcare workers. 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.
