Synthetic cannabinoid receptor agonists (SCRAs) are novel psychoactive substances that bind to and activate CB1 receptors in the brain. The structural manipulations observed in newer SCRAs suggest that manufacturers have incorporated modern drug development techniques into their repertoire, often producing higher CB1 receptor affinity than Δ9-tetrahydrocannabinol (Δ9-THC). This study examined nine SCRAs recently detected by forensic surveillance, some of which caused fatalities: 5F-MDMB-PICA, FUB-144, 5F-MMB-PICA, MMB-4en-PICA, MMB-FUBICA, 5F-EDMB-PINACA, APP-BINACA, MDMB-4en-PINACA, and FUB-AKB48. Compounds were evaluated for CB1 and CB2 receptor binding affinity and functional activation and for their effects on body temperature, time course, and pharmacological equivalence with Δ9-THC in Δ9-THC drug discrimination in mice. All SCRAs bound to and activated CB1 and CB2 receptors with high affinity, with similar or greater affinity for CB2 than CB1 receptors and stimulated [35S]GTPγS binding in CB1 and CB2 expressing cell membranes. All compounds produced hypothermia, with shorter latency to peak effects for SCRAs than Δ9-THC. All SCRAs fully substituted for Δ9-THC in drug discrimination at one or more doses. Rank order potency in producing in vivo effects mostly aligned with rank order CB1 receptor affinities. Potencies for Δ9-THC-like discriminative stimulus effects were similar across sex except Δ9-THC was more potent in females and 5F-MMB-PICA was more potent in males. In summary, 5F-EMDB-PINACA, 5F-MDMB-PICA, MDMB-4en-PINACA, FUB-144, FUB-AKB48, 5F-MMB-PICA, MMB-4en-PICA, and MMB-FUBICA are potent and efficacious SCRAs with pharmacology like that of past SCRAs that have been abused in humans. In contrast, APP-BINACA was efficacious, but had lower potency than most past SCRAs.
