In vitro activity-profiling of Cumyl-PEGACLONE variants at the CB1 receptor: fluorination versus isomer exploration.
Drug Test Anal. 2020 Jun 03;:
Authors: Janssens L, Cannaert A, Connolly MJ, Liu H, Stove CP
Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest groups of new psychoactive substances (NPS) monitored in Europe. SCRAs are known to typically exert higher cannabinoid activity than THC from cannabis, therefore entailing a greater health risk. Both Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE were not controlled by the national legislation upon their first detection in Germany in 2016 and 2017, respectively, and have been linked to several fatalities. In this study, the CB1 receptor activity of these compounds, together with two newly synthesized structural isomers (Cumyl-PEGACLONE ethylbenzyl isomer and n-propylphenyl isomer) was assessed using two different in vitro receptor-proximal bio-assays, monitoring the recruitment of either β-arrestin2 or a modified G protein (mini-Gαi ) to the activated CB1 receptor. Both in terms of potency and relative efficacy, Cumyl-PEGACLONE and 5F-Cumyl-PEGACLONE were found to exert strong CB1 activation, with sub-nanomolar EC50 values, and efficacy values exceeding those of the reference agonist JWH-018 >3 fold (β-arrestin2 assay) or almost 2-fold (mini-Gαi assay). The ethylbenzyl and n-propylphenyl isomers showed a strongly reduced CB1 activity (EC50 values >100 nM; efficacy <40% relative to JWH-018), which is hypothesized to originate from steric hindrance in the ligand binding pocket. Therefore, their abuse potential seems less likely. None of the evaluated compounds showed significant biased agonism. In conclusion, the functional assays applied here allowed us to demonstrate that 5-fluorination of Cumyl-PEGACLONE is not linked to an intrinsically higher CB1 activation potential, and that the ethylbenzyl and n-propylphenyl isomers yield a strongly reduced CB1 activitation.
PMID: 32490586 [PubMed – as supplied by publisher]
Source: ncbi 2