Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists

Diversion of synthetic cannabinoids from the lab to drugs of abuse has become increasingly prevalent in recent years. Moreover, as earlier synthetic cannabinoids were banned, manufacturers introduced a new supply of novel compounds to serve as replacements. Hence, the chemical diversity of synthetic cannabinoid analogs has also rapidly increased. The present study examined 8 new synthetic cannabinoids: AM-1220, AM-2232, AM-2233, AM-679, EAM-2201, JWH-210, JHW-251, and MAM-2201. Each compound was assessed for binding affinity and functional activation of CB₁ and CB₂ receptors, and pharmacological equivalence with Δ⁹-tetrahydrocannabinol (THC) in THC drug discrimination. All compounds bound to and activated CB₁ and CB₂ receptors, although efficacy at the CB₂ receptor was reduced compared to that for the CB₁ receptor. Similarly, all compounds stimulated [³⁵S]GTPγS binding through the CB₁ receptor, and all compounds except AM-1220 and AM-2233 stimulated [³⁵S]GTPγS binding through the CB₂ receptor. Furthermore, these compounds, along with CP55,940, substituted for THC in THC drug discrimination. Rank order of potency in drug discrimination was correlated with CB₁ receptor binding affinity. Together, these results suggest that all test compounds share the THC-like subjective effects of marijuana. Interestingly, the most potent compounds in CB₁ binding in the present study were also the compounds that have been found recently in the U.S., MAM-2201, EAM-2201, JWH-210, AM-2233, and AM-1220. These results indicate that the evolution of the synthetic cannabinoid drug market may be focused toward compounds with increased potency. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'