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Do toxic synthetic cannabinoid receptor agonists have signature in vitro activity profiles? A case study of AMB-FUBINACA.

Recreational consumption of synthetic cannabinoid receptor agonists (SCRAs) is a growing crisis in public health, in many parts of the world. AMB-FUBINACA is a member of this class of drugs, and is responsible for a large proportion of SCRA-related toxicity both in New Zealand and internationally. Strikingly, little is currently known about the mechanisms by which SCRAs exert toxic effects - nor whether their activity through the CB1 cannabinoid receptor (the mediator of cannabinoid-related psychoactivity) are sufficient to explain clinical observations. The current study therefore set out to perform a basic molecular pharmacology characterization of AMB-FUBINACA (in comparison to traditional research cannabinoids CP55,940, WIN55,212-2, and Δ9-THC) in fundamental pathways of receptor activity, including cAMP inhibition, pERK activation, ability to drive CB1 internalization, and ability to induce translocation of β-arrestins 1 and -2. Activity pathways were then compared by Operational analysis, to indicate whether AMB-FUBINACA may be a biased ligand. Results revealed that AMB-FUBINACA is highly efficacious and potent in all pathways assayed. However, surprisingly, bias analysis suggested that Δ9-THC, not AMB-FUBINACA, may be a biased ligand - being less active in both arrestin pathways than predicted by the activity of the other ligands tested. These data may help predict molecular characteristics of SCRAs. However, more research is required to determine whether these molecular effects manifest in toxicity at tissue/system level.