Off-target pharmacological profiling of synthetic cannabinoid receptor agonists including AMB-FUBINACA, CUMYL-PINACA, PB-22, and XLR-11

Richard C Kevin; Elizabeth A Cairns; Rochelle Boyd; Jonathon C Arnold; Michael T Bowen; Iain S McGregor; Samuel D Banister

doi:10.3389/fpsyt.2022.1048836

Off-target pharmacological profiling of synthetic cannabinoid receptor agonists including AMB-FUBINACA, CUMYL-PINACA, PB-22, and XLR-11

Front Psychiatry. 2022 Dec 15:13:1048836. doi: 10.3389/fpsyt.2022.1048836. eCollection 2022.

Authors

Richard C Kevin^{1

2}, Elizabeth A Cairns^{1

3}, Rochelle Boyd^{1

3}, Jonathon C Arnold^{1

2}, Michael T Bowen^{3

4}, Iain S McGregor^{1

3}, Samuel D Banister^{1

5}

Affiliations

¹ The Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Camperdown, NSW, Australia.
² School of Pharmacy, The University of Sydney, Camperdown, NSW, Australia.
³ School of Psychology, The University of Sydney, Camperdown, NSW, Australia.
⁴ Brain and Mind Centre, The University of Sydney, Camperdown, NSW, Australia.
⁵ School of Chemistry, The University of Sydney, Camperdown, NSW, Australia.

Abstract

Introduction: Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances that have been associated with multiple instances and types of toxicity. Some SCRAs appear to carry a greater toxicological burden than others, or compared to the prototypical cannabis-derived agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC), despite a common primary mechanism of action via cannabinoid 1 (CB1) receptors. "Off-target" (i.e., non-CB1 receptor) effects could underpin this differential toxicity, although there are limited data around the activity of SCRAs at such targets.

Methods: A selection of 7 SCRAs (AMB-FUBINACA, XLR11, PB-22, AKB-48, AB-CHMINICA, CUMYL-PINACA, and 4F-MDMB-BUTINACA), representing several distinct chemotypes and toxicological profiles, underwent a 30 μM single-point screen against 241 G protein-coupled receptor (GPCR) targets in antagonist and agonist mode using a cellular β-arrestin recruitment assay. Strong screening "hits" at specific GPCRs were followed up in detail using concentration-response assays with AMB-FUBINACA, a SCRA with a particularly notable history of toxicological liability.

Results: The single-point screen yielded few hits in agonist mode for any compound aside from CB1 and CB2 receptors, but many hits in antagonist mode, including a range of chemokine receptors, the oxytocin receptor, and histamine receptors. Concentration-response experiments showed that AMB-FUBINACA inhibited most off-targets only at the highest 30 μM concentration, with inhibition of only a small subset of targets, including H₁ histamine and α_2B adrenergic receptors, at lower concentrations (≥1 μM). AMB-FUBINACA also produced concentration-dependent CB1 receptor signaling disruption at concentrations higher than 1 μM, but did not produce overt cytotoxicity beyond CP55,940 or Δ⁹-THC in CB1 expressing cells.

Discussion: These results suggest that while some "off-targets" could possibly contribute to the SCRA toxidrome, particularly at high concentrations, CB1-mediated cellular dysfunction provides support for hypotheses concerning on-target, rather than off-target, toxicity. Further investigation of non-GPCR off-targets is warranted.

Keywords: AMB-FUBINACA; G protein coupled receptor (GPCR); SCRA; cannabinoid; off-target; synthetic; toxicity.