Do Toxic Synthetic Cannabinoid Receptor Agonists Have Signature in Vitro Activity Profiles? A Case Study of AMB-FUBINACA

Abstract

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 or whether their activity through the CB 1 cannabinoid receptor (the mediator of cannabinoid-related psychoactivity) is 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 Δ 9 -THC) in fundamental pathways of receptor activity, including cAMP inhibition, pERK activation, ability to drive CB 1 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 Δ 9 -THC, not AMB-FUBINACA, may be a biased ligand, with it 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.

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“…Canonically, β‐arrestins are known to be involved in GPCR internalization, however recent reports suggest that arrestins may also be responsible for certain G protein‐independent responses . The latter finding has prompted the notion that SCRA‐mediated activation of β‐arrestin ‐1 and ‐2 may play an important role in SCRA toxicity . Notwithstanding, the exact mechanism(s) of observed SCRA toxicity remains largely elusive.…”

New psychoactive substances: a review and updates

“…Synthetic cannabinoids do not contain cannabidiol (the main neuro-protective compound found in natural cannabis which predominantly acts on CB2 receptors) and this may also be related to the increased toxicity observed with these compounds compared with natural cannabis. 95,96 Synthetic cannabinoids have a greater potency and binding affinity than d9-THC at the cannabinoid receptors. They are full agonists compared with the partial agonist properties of d9-THC, with potency of 10-200 times greater than that of d9-THC.…”

“…These differences likely underpin the emerging greater incidence of major psychiatric complications and other adverse effects compared with traditional cannabis. [96][97][98][99] A self-reported survey of 80,000 illicit substance users revealed that those who used synthetic cannabinoids were 30 times more likely to end up in an emergency department than users of traditional cannabis. 79 Harms and adverse effects There is currently no evidence for any therapeutic potential of synthetic cannabinoids with overwhelming reports of mild to severe adverse effects.…”

“…Synthetic cannabinoids do not contain cannabidiol (the main neuro-protective compound found in natural cannabis which predominantly acts on CB2 receptors) and this may also be related to the increased toxicity observed with these compounds compared with natural cannabis. 95 , 96 …”

Differential activation of G protein‐mediated signaling by synthetic cannabinoid receptor agonists

“…The mechanism(s) through which SCRAs exert different behavioral and physiological effects remains unclear, and which pathways modulated by CB1 activation mediate the specific pharmacological effects of SCRAs is also unknown. Similarly, the question of whether these pathways are activated in a quantitatively or qualitatively similar way by SCRAs and THC is only beginning to be addressed . Finally, the question of whether SCRA activity at noncannabinoid receptors is also important for their pharmacological effects is very much open .…”