Cannabimimetic activities of cumyl carboxamide-type synthetic cannabinoids

1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide (CUMYL-PINACA) is a carboxamide-type synthetic cannabinoid comprising a cumylamine moiety. Recently, the detection of CUMYL-PINACA and some analogs in illicit drug products has been reported by the European Monitoring Centre for Drugs and Drug Addiction. In this study, we synthesized seven cumyl carboxamide-type synthetic cannabinoids (CUMYL-PINACA, CUMYL-5F-PINACA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-THPINACA, CUMYL-BICA, and CUMYL-5F-P7AICA) and evaluated their activities as CB₁ and CB₂ receptor agonists. We also showed the analytical characterization of these compounds using gas chromatography–electron ionization-mass spectrometry. All of the evaluated compounds exhibited moderate to strong activities as agonists acting on both CB₁ and CB₂ receptors with EC₅₀ values in the range of 8.1 × 10⁻¹⁰–7.8 × 10⁻⁷ mol/L for CB₁ and from 2.5 × 10⁻¹⁰ to 9.1 × 10⁻⁶ mol/L for CB₂. The EC₅₀ data presented will be helpful to understand the effects of these compounds in the forensic cases. Furthermore, other new cumyl carboxamide-type synthetic cannabinoids, which will be potentially distributed in the future, will probably have the activities as agonists acting on both CB₁ and CB₂ receptors.