Investigation of the intrinsic cannabinoid activity of hemp-derived and semisynthetic cannabinoids with β-arrestin2 recruitment assays-and how this matters for the harm potential of seized drugs.

Autor: Janssens LK; Laboratory of Toxicology, Department of Bioanalysis - Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium., Van Uytfanghe K; Laboratory of Toxicology, Department of Bioanalysis - Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium., Williams JB; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, 48108, USA., Hering KW; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, 48108, USA., Iula DM; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, 48108, USA., Stove CP; Laboratory of Toxicology, Department of Bioanalysis - Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium. christophe.stove@ugent.be.
Jazyk: angličtina
Zdroj: Archives of toxicology [Arch Toxicol] 2024 Aug; Vol. 98 (8), pp. 2619-2630. Date of Electronic Publication: 2024 May 12.
DOI: 10.1007/s00204-024-03769-4
Abstrakt: Cultivation of industrial low-Δ 9 -tetrahydrocannabinol (Δ 9 -THC) hemp has created an oversupply of cannabidiol (CBD)-rich products. The fact that phytocannabinoids, including CBD, can be used as precursors to synthetically produce a range of THC variants-potentially located in a legal loophole-has led to a diversification of cannabis recreational drug markets. 'Hemp-compliant', 'hemp-derived' and 'semisynthetic' cannabinoid products are emerging and being advertised as (legal) alternatives for Δ 9 -THC. This study included a large panel (n = 30) of THC isomers, homologs, and analogs that might be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB 1 cannabinoid receptor with a β-arrestin2 recruitment bioassay (picomolar-micromolar concentrations). Multiple THC homologs (tetrahydrocannabihexol, THCH; tetrahydrocannabiphorol, THCP; tetrahydrocannabinol-C8, THC-C8) and THC analogs (hexahydrocannabinol, HHC; hexahydrocannabiphorol, HHCP) were identified that showed higher potential for CB 1 activation than Δ 9 -THC, based on either higher efficacy (E max ) or higher potency (EC 50 ). Structure-activity relationships were assessed for Δ 9 -THC and Δ 8 -THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB 1 activity were established for various THC isomers (Δ 7 -THC, Δ 10 -THC) and analogs (HHC, HHCP). Evaluation of the relative abundance of 9(S)-HHC and 9(R)-HHC epimers in seized drug material revealed varying epimeric compositions between batches. Increased abundance of the less active 9(S)-HHC epimer empirically resulted in decreased potency, but sustained efficacy for the resulting diastereomeric mixture. In conclusion, monitoring of semisynthetic cannabinoids is encouraged as the dosing and the relative composition of stereoisomers can impact the harm potential of these drugs, relative to Δ 9 -THC products.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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