AUTHOR=Kevin Richard C. , Anderson Lyndsey , McGregor Iain S. , Boyd Rochelle , Manning Jamie J. , Glass Michelle , Connor Mark , Banister Samuel D. 

TITLE=CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00595

DOI=10.3389/fphar.2019.00595

ISSN=1663-9812

ABSTRACT=<p>Synthetic cannabinoid receptor agonists (SCRAs) are the largest class of new psychoactive substances (NPS). New examples are detected constantly, and some are associated with a series of adverse effects, including seizures. CUMYL-4CN-BINACA (1-(4-cyanobutyl)-<italic>N</italic>-(2-phenylpropan-2-yl)indazole-3-carboxamide) is structurally related to potent, cumylamine-derived SCRAs such as 5F-CUMYL-PINACA, but is unusual due to a terminal aliphatic nitrile group not frequently encountered in SCRAs or pharmaceuticals. We report here that CUMYL-4CN-BINACA is a potent CB<sub>1</sub> receptor agonist (<italic>K</italic><sub>i</sub> = 2.6 nM; EC<sub>50</sub> = 0.58 nM) that produces pro-convulsant effects in mice at a lower dose than reported for any SCRA to date (0.3 mg/kg, i.p). Hypothermic and pro-convulsant effects in mice could be reduced or blocked, respectively, by pretreatment with CB<sub>1</sub> receptor antagonist SR141716, pointing to at least partial involvement of CB<sub>1</sub> receptors <italic>in vivo</italic>. Pretreatment with CB2 receptor antagonist AM-630 had no effect on pro-convulsant activity. The pro-convulsant properties and potency of CUMYL-4CN-BINACA may underpin the toxicity associated with this compound in humans.</p>