TY - JOUR T1 - Pharmacodynamic effects, pharmacokinetics, and metabolism of the synthetic cannabinoid AM-2201 in male rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.250530 SP - jpet.118.250530 AU - Jeremy Carlier AU - Ariane Wohlfarth AU - Bonita D Salmeron AU - Karl B Scheidweiler AU - Marilyn A Huestis AU - Michael H Baumann Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/09/28/jpet.118.250530.abstract N2 - Novel synthetic cannabinoids are appearing in recreational drug markets worldwide. Pharmacological characterization of these new drugs is needed to inform clinicians, toxicologists and policy makers who monitor public health. 1-[(5-Fluoropentyl)-1H-indol-3-yl]-(naphthalen-1-yl)methanone (AM-2201) is an abused synthetic cannabinoid that was initially created as a research tool for investigating the endocannabinoid system. Here we measured pharmacodynamic effects of AM-2201 in rats, and simultaneously determined plasma pharmacokinetics for the parent drug and its metabolites. Male Sprague-Dawley rats were fitted with surgically-implanted temperature transponders and indwelling jugular catheters under pentobarbital anesthesia. One week later, rats received subcutaneous (sc) injection of AM-2201 (0.1, 0.3 and 1.0 mg/kg) or its vehicle, and serial blood specimens were withdrawn via catheters. Core temperatures and catalepsy were measured just prior to each blood withdrawal, and plasma was assayed for drug and metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that AM-2201 produced dose-related hypothermia and catalepsy that peaked at 2 h and lasted up to 8 h. AM-2201 plasma concentrations rose linearly with increasing dose and ranged from 0.14 – 67.9 µg/L. Concentrations of three metabolites, AM-2201 N-(4-hydroxypentyl) (≤0.17 µg/L), naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) N-(5-hydroxypentyl) (≤1.14 µg/L) and JWH-018 N-pentanoic acid (≤0.88 µg/L) were detectable but much lower. Peak AM-2201, JWH-018 N-(5-hydroxypentyl), and JWH-018 N-pentanoic acid concentrations occurred at 1.3, 2.4 and 6.5 h, respectively. Concentrations of AM-2201, JWH-018 N-(5-hydroxypentyl) and JWH-018 N-pentanoic acid were negatively correlated with body temperature, but given the low concentrations of metabolites detected, AM-2201 is likely the major contributor to pharmacodynamic effects under our experimental conditions. ER -