TY - JOUR T1 - Synthetic cannabinoid hydroxypentyl metabolites retain efficacy at human cannabinoid receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.254425 SP - jpet.118.254425 AU - Thomas F Gamage AU - Charlotte E Farquhar AU - Ryan J McKinnie AU - Richard C Kevin AU - Iain S McGregor AU - Mark Trudell AU - Jenny L Wiley AU - Brian F Thomas Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/12/14/jpet.118.254425.abstract N2 - Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. While the structures of these compounds are based upon scaffolds with known affinity and efficacy at the human cannabinoid type-1 receptor (hCB1), upon ingestion or inhalation they can be metabolized to multiple chemical entities of unknown pharmacological activity. A large proportion of these metabolites are hydroxylated on the pentyl chain, a key substituent that determines receptor affinity and selectivity. Thus, the pharmacology of SC metabolites may be an important component in understanding the in vivo effects of SCs. We examined nine SCs (AB-PINACA, 5F-AB-PINACA, ADB/MDMB-PINACA, 5F-ADB, 5F-CUMYL-PINACA, AMB-PINACA, 5F-AMB, APINACA, and 5F-APINACA) and their hydroxypentyl (either 4-OH or 5-OH) metabolites in [3H]CP55,940 receptor binding and the [35S]GTPĪ³S functional assay to determine the extent to which these metabolites retain activity at cannabinoid receptors. All of the SCs tested exhibited high affinity (<10 nM) and efficacy for hCB1 and hCB2. The majority of the hydroxypentyl metabolites retained full efficacy at hCB1 and hCB2, albeit with reduced affinity and potency, and exhibited greater binding selectivity for hCB2. These data suggest that phase I metabolites may be contributing to the in vivo pharmacology and toxicology of abused SCs. Considering this and previous reports demonstrating that metabolites retain efficacy at the hCB1 receptor, the full pharmacokinetic profile of the parent compounds and their metabolites needs to be considered in terms of the pharmacological effects and time course associated with these drugs. ER -