Synthetic cannabimimetics with cyclobutyl methyl and norbornyl methyl side chains – Pharmacological data and legislative implications

Abstract

Structural elucidation and analytical characterization of six newly emerged synthetic cannabimimetics (SCs) carrying a cyclobutyl methyl (CBM) or a norbornyl methyl (NBM) side chain were performed within the ADEBAR project. Pharmacological evaluation allowed for estimating in vivo cannabimimetic activities as required in many countries for the amendment of laws controlling these substances. SCs, one of the largest subgroups of new psychoactive substances (NPS), possess a unique dynamic in Germany, where new variants have been observed to circumvent national legislation. In 2019–2020, the CBM moiety was identified as a new side chain in three SCs, leading to substances not covered by the German new psychoactive substances act (NpSG) at that time. In the following year, indole, indazole, and γ-carbolinone SCs featuring a NBM side chain were detected shortly after an amendment of the NpSG covering the CBM side chain. The introduction of these moieties that were not described in the synthetic cannabinoid research literature prior to their appearance on the drug market underpins the creativity of drug designers, obviously motivated by a recent amendment of the German NpSG. Analytical characterization of six SCs carrying a CBM or a NBM side chain was performed using GC-MS, ATR-FT-(N)IR, GC-sIR, NMR, LC-(HR)MS, and Raman spectroscopy. Binding affinities and functional activities were studied at the cannabinoid receptor 1 (CB1) using filtration-based radioligand assays. All six SCs showed full agonist properties at the CB1 receptor compared to Δ9-THC and CP-55940. The three SCs carrying a CBM group showed binding affinities from 29.4 to 0.65 nM (CBMICA >> CBMINACA > CBMeGaClone). The potencies of the compounds increased in the same order (EC50: 483–40.1 nM), which also reflects the order of their occurrence on the drug market. The norbornyl derivatives exhibit higher affinities (Ki: 1.87–0.25 nM), with the indazole derivative exhibiting the highest affinity. Functional activity data confirmed the indazole being the most potent and efficacious of these three NBM SCs (EC50: 169-–1.78 nM). The binding affinities and potencies were significantly increased by the introduction of the relatively voluminous norbornyl side chain. Only the γ-carbolinone analog exhibited a slight decrease of the binding affinity from 0.65 to 2.4 nM when exchanging the CBM group for the NBM group. Still, potency increased by factor 4 (indole: factor 2, indazole: factor 31). Cumyl-CBMICA showed the lowest binding affinity and functional activity of the six compounds. Interestingly, the average concentration of Cumyl-CBMICA increased from 5 mg/g to 71 mg/g in commercially available ‘herbal blends’ between July 2019 and December 2019 ( n = 14 blends analyzed) and the herbal blend product with the highest concentration was advertised as “strong” in the online shop. The concentrations were likely increased in the herbal blends due to the low potency of Cumyl-CBMICA in vivo, which has also been reported by user feedback given in online forums. New CBM and NBM SCs have been detected by the ADEBAR project in Germany and the six investigated SCs showed to act as full agonists at the CB1 receptor. The pharmacological data underpin their abuse potential and facilitated the legislative amendments to the German NpSG.