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In vitro determination of the CB1 efficacy of illicit synthetic cannabinoids

By Shivani Sachdev, Kiran Vemuri, Samuel D. Banister, Mitchell Longworth, Michael Kassiou, Marina Santiago, Alexandros Makriyannis, Mark Connor

Posted 06 Aug 2018
bioRxiv DOI: 10.1101/385583 (published DOI: 10.1111/bph.14829)

BACKGROUND AND PURPOSE: The morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) is a major health concern, and may involve over-activation of CB1 receptors. Thus, we sought to determine the efficacy of 13 SCRAs at CB1 using receptor depletion with the irreversible CB1 antagonist AM6544 followed by fitting the curve with the Black and Leff operational model to calculate efficacy. EXPERIMENTAL APPROACH: Receptor depletion in mouse AtT-20 neuroblastoma cells stably expressing human CB1 was achieved by pre-treatment of cells with AM6544 (10 µM, 60 mins). The CB1-mediated hyperpolarisation of AtT20 cells was measured using membrane potential dye. From data fit to the operational model, the efficacy (tau) and affinity (KA) parameters were obtained for each drug. KEY RESULTS: AM6544 did not affect the potency or maximal effect of native somatostatin receptor-induced hyperpolarisation (Control, pEC50 9.13 ± 0.05, Emax 38 ± 1%; AM6544 treated pEC50 9.18 ± 0.04, Emax 39 ± 0.7%). The tau value of Δ9-THC was 70-fold less than the reference CB-agonist CP55940, and 240-fold less than the highest efficacy SCRA, 5F-MDMB-PICA. Most of the SCRAs had about 50% of the efficacy of CP55940. There was no correlation between the tau and KA values for any SCRA. CONCLUSION AND IMPLICATIONS: All the SCRA tested showed substantially higher agonist activity at CB1 than Δ9-THC, which may contribute to the adverse effects seen with these drugs but not Δ9-THC, although the mechanisms underlying SCRA toxicity are still poorly defined.

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