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](1-naphthyl)methanone (AM-2201) is an abused synthetic
cannabinoid that was initially created as a research tool for investigating the
endocannabinoid system. Here we measured the 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 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AM-2201 (0.1, 0.3, and 1.0 mg/kg) or its vehicle, and serial blood specimens were withdrawn via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. We found that
AM-2201 produced dose-related
hypothermia and
catalepsy that peaked at 2 hours and lasted up to 8 hours.
AM-2201 plasma concentrations rose linearly with increasing dose and ranged from 0.14 to 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 hours, 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.