In Vitro Characterization of the Pyrazole-Carrying Synthetic Cannabinoid Receptor Agonist 5F-3,5-AB-PFUPPYCA and its Structural Analogs

Pyrazole-carrying “FUPPYCA” synthetic cannabinoid receptor agonists (SCRAs) have made short-lived appearances on the market since 2015. However, 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA have recently been detected in Scottish prisons. This re-emergence is believed to be triggered by the Chinese generic SCRA ban (2021). Infused paper samples, seized from different Scottish prisons were analyzed to assess the prevalence of FUPPYCA SCRAs. Six structurally related analogs were then functionally characterized using live cell receptor-based assays, based on the functional complementation of a nanoluciferase enzyme. 5F-3,5-AB-PFUPPYCA and 3,5-ADB-4en-PFUPPYCA mixtures were detected 9 times in Scottish prisons since July 2021. Most FUPPYCA SCRAs were found to be inactive at both CB1 and CB2, with only 3 analogs showing some (minor) CB1 activation potential (3,5-AB-CHMFUPPYCA, 5,3-AB-CHMFUPPYCA and 5,3-ADB-4en-PFUPPYCA). Interestingly, the 5,3 regioisomers (covered by the ban) were more active than their 3,5 counterparts. Furthermore, all analogs had antagonistic properties, potentially related to their structural resemblance to cannabinoid antagonists. Given their weak CB activity, FUPPYCA SCRAs are not expected to pose a serious health hazard, despite their ability to evade the generic ban. This may also explain their only transient re-emergence in Scottish prisons.