Pharmacological characterization of emerging synthetic cannabinoids in HEK293T cells and hippocampal neurons.
There has been a worldwide proliferation of synthetic cannabinoids that have become marketed as legal alternatives to cannabis (marijuana). Unfortunately, there is a dearth of information about the pharmacological effects of many of these emerging synthetic cannabinoids (ESCs), which presents a challenge for regulatory authorities that need to take such scientific evidence into consideration in order to regulate ECSs as controlled substances. We aimed to characterize the pharmacological properties of ten ESCs using two cell based assays that enabled the determination of potency and efficacy relative to a panel of well-characterized cannabinoids. Agonist-mediated inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live HEK293T cells transfected with human cannabinoid receptor 1 gene (CNR1) and pGloSensor-22F. Pharmacological analysis of this data indicated that all of the ESCs tested were full agonists, with the following rank order of potency: Win 55212-2≈5F-PB-22≈AB-PINACA≈EAM-2201≈MAM-2201>JWH-250≈ PB-22>AKB48 N-(5FP)>AKB-48≈STS-135>XLR-11. Assessment of agonist-stimulated depression of Ca(2+) transients was also used to confirm the efficacy of five ESCs (XLR-11, JWH-250, AB-PINACA, 5F-PB-22, and MAM-2201) in cultured primary hippocampal neurons. This work aims to help inform decisions made by regulatory agencies concerned with the profusion of these poorly characterized recreational drugs.
Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
Willard J
WJ
Costain
Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
Joseph S
JS
Tauskela
Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
Ingrid
I
Rasquinha
Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
Tanya
T
Comas
Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6.
Melissa
M
Hewitt
Office of Research and Surveillance, Controlled Substances and Tobacco Directorate, Healthy Environments and Consumer Safety Branch, Health Canada, 150 Tunney's Pasture Driveway, Ottawa, Ontario, Canada K1A 0K9.
Vincent
V
Marleau
Office of Research and Surveillance, Controlled Substances and Tobacco Directorate, Healthy Environments and Consumer Safety Branch, Health Canada, 150 Tunney's Pasture Driveway, Ottawa, Ontario, Canada K1A 0K9. Electronic address: evelyn.soo@canada.ca.
Evelyn C
EC
Soo
D000818:Animals; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D002186:Cannabinoids
5F-PB-22 (PubChem CID: 72710774); AB-PINACA (PubChem CID: 71301472); AKB-48 (PubChem CID: 57404063); AKB48 N-(5FP) (PubChem CID: 71711119); Calcium; Cannabinoid receptor; EAM-2201 (PubChem CID: 71308187); HEK293; JWH-250 (PubChem CID: 44397540); MAM-2201 (PubChem CID: 66570720); Neurons; PB-22 (PubChem CID: 71604304); STS-135 (PubChem CID: 57404059); Synthetic cannabinoid; XLR-11 (PubChem CID: 57501498); cAMP