Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors
Christian V. Cabanlong, Lauren Russell, William E. Fantegrossi, Paul L. Prather
Abstract
Synthetic cannabinoid receptor agonists (SCRAs) are a large group of abused psychoactive compounds that elicit numerous toxic effects not observed with cannabis, including death. Abuse of third-generation SCRA 5F-MDMB-PINACA (also known as 5F-ADB) has been associated with over 40 fatalities. This SCRA is metabolized to several active phase I metabolites, including excessively high post-mortem serum concentrations of an ester hydrolysis metabolite, 5F-MDMB-PINACA-M7 (M7). Although high serum concentrations of M7 (and other active metabolites) have been suggested to contribute to 5F-MDMB-PINACA toxicity, the affinity of M7 for CB1 receptors is unknown and more complete pharmacodynamic characterization of 5F-MDMB-PINACA and its active metabolites is needed. Competition binding and G-protein modulation studies presented here confirm reports that 5F-MDMB-PINACA and a second N-5-hydroxypentyl metabolite (M2) exhibit nM affinity and act as high efficacy agonists at CB1 receptors. Also as previously published, M7 exhibits high efficacy at CB1 receptors; however, demonstrated here for the first time, M7 retains only low μΜ affinity. Empirically derived Kb values indicate rimonabant differentially antagonizes G-protein activation produced by 5F-MDMB-PINACA, relative to Δ9-THC (THC) or its metabolites. Chronic administration of 5F-MDMB-PINACA and metabolites results in CB1 down-regulation, but only 5F-MDMB-PINACA produces desensitization. Although low CB1 affinity/potency of M7 precluded in vivo studies, both M2 and THC produce locomotor suppression and CB1-mediated dose-dependent hypothermia and analgesia in mice. Collectively, these data confirm and extend previous studies suggesting that 5F-MDMB-PINACA is metabolized to active compounds exhibiting atypical pharmacodynamic properties at CB1 receptors, that may accumulate with parent drug to produce severe toxicity.