Pharmacological Characterization of Synthetic Cannabinoid MAM‐2201: Radioligand Binding and Abuse‐Related Effects

Abstract

Abuse of novel psychoactive substances (NPS) is growing at an alarming rate worldwide, and over 30% of all NPS identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids. The recent emergence of MAM‐2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature, and thus appears to be a novel compound developed specifically as a “gray market” drug of abuse. Structurally, MAM‐2201 is a hybrid of two known synthetic cannabinoid compounds (JWH‐122 and AM‐2201) and therefore presumably acts as a high‐efficacy agonist at cannabinoid receptors, but its pharmacological properties are unknown. Thus, the present studies characterized its cannabinoid‐like activities in vitro and in vivo. In a radioligand binding assay using [3H]CP55,940 in HEK cell membranes transfected with the cannabinoid type 1 receptor (CB1R), MAM‐2201 (Ki = 5.4 nM), similar to WIN 55,212‐2 (Ki = 8.3 nM), had higher binding affinity for CB1R than Δ9‐THC (Ki = 80.1 nM). The Emax values for MAM‐2201 and WIN 55‐212‐2 in an assay of agonist inhibition of forskolin‐stimulated cAMP were 85% (EC50 = 0.45 nM) and 94%, respectively, as compared with the Δ9‐THC Emax of 74%. In mice, MAM‐2201 (0.003‐1.0 mg/kg, I.P., N=8 per group) produced dose‐dependent effects in all measures of the cannabinoid tetrad, which were both more potent and more effective than those of Δ9‐THC. MAM‐2201 and Δ9‐THC dose‐dependently produced the following cannabinoid‐like effects (1) hypothermia: ED50 = 0.287 and 25.4 mg/kg, (2) analgesia: ED50 = 0.125 and 29.4 mg/kg, (3) catalepsy: ED50 = 0.301 and 18.9 mg/kg, and (4) hypolocomotion: ED50 = 0.782 and >100 mg/kg, respectively in adult male CD1 mice. Pronounced strain differences between CD1 and C57Bl6/J animals were noted for hypolocomotor effects, and the CB1 antagonist rimonabant attenuated all of these effects. In rats, MAM‐2201 produced dose‐dependent Δ9‐THC‐like interoceptive effects in subjects trained to discriminate 3.0 mg/kg (IP) Δ9‐THC from saline, and rimonabant attenuated these effects as well. Thus, MAM‐2201 functioned as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species. Importantly, MAM‐2201 also elicited convulsant effects at a dose of 1.0 mg/kg in 8/8 murine subjects. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Drug Enforcement Administration or the Food and Drug Administration.Support or Funding InformationSupported by the Drug Enforcement Administration, National Center for Toxicological Research (protocol # E0763601) and University of Arkansas for Medical Sciences.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.