Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors.

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.