In vitro and in vivo pharmacology of nine novel synthetic cannabinoid receptor agonists

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.