LAUSR

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 7 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 - 721 nM at CB1 and 2.21 - 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 HPLC-DAD, GC-MS, LC-QTOF-MS and FTIR and 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.