Cannabinoid receptor activation potential of the next generation, generic ban evading OXIZID synthetic cannabinoid receptor agonists

In recent years, several nations have implemented various measures to control the surge of new synthetic cannabinoid receptor agonists (SCRAs) entering the recreational drug market. In July 2021, China put into effect a new generic legislation, banning SCRAs containing one of seven general core scaffolds. However, this has driven manufacturers towards the synthesis of SCRAs with alternative core structures, exemplified by the recent emergence of “OXIZID SCRAs.” Here, using in vitro β‐arrestin2 recruitment assays, we report on the CB1 and CB2 potency and efficacy of five members of this new class of SCRAs: BZO‐HEXOXIZID, BZO‐POXIZID, 5‐fluoro BZO‐POXIZID, BZO‐4en‐POXIZID, and BZO‐CHMOXIZID. All compounds behaved as full agonists at CB1 and partial agonists at CB2. Potencies ranged from 84.6 to 721 nM at CB1 and 2.21 to 25.9 nM at CB2. Shortening the n‐hexyl tail to a pentyl tail enhanced activity at both receptors. Fluorination of this pentyl analog did not yield a higher receptor activation potential, whereas an unsaturated tail resulted in decreased potency and efficacy at CB1. The cyclohexyl methyl analog BZO‐CHMOXIZID was the most potent compound at both receptors, with EC50 values of 84.6 and 2.21 nM at CB1 and CB2, respectively. Evaluation of the activity of a seized powder containing BZO‐4en‐POXIZID suggested a high purity, in line with high‐performance liquid chromatography coupled to diode‐array detection (HPLC‐DAD), gas chromatography coupled to mass spectrometry (GC–MS), liquid chromatography coupled to time‐of‐flight mass spectrometry (LC‐QTOF‐MS), and Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) analysis. Furthermore, all tested compounds showed a preference for CB2, except for BZO‐POXIZID. Overall, these findings inform public health officials, law enforcement agencies, and clinicians on these newly emerging SCRAs. Since the 2021 Chinese generic ban of SCRAs, compounds carrying unexpected core structures appeared in the illicit drug landscape. Cannabinoid activity at CB1 and CB2 of five newly emerging “OXIZID” SCRAs was assessed using live cell‐based β‐arrestin2 recruitment assays. All compounds activated both CB1 and CB2, and all but one showed a preference for CB2, despite their identification in seized materials.