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Shape matters: The application of activity‐based in vitro bioassays and chiral profiling to the pharmacological evaluation of synthetic cannabinoid receptor agonists in drug‐infused papers seized in prisons
Author(s) -
Antonides Lysbeth H.,
Cannaert Annelies,
Norman Caitlyn,
NicDáeid Niamh,
Sutcliffe Oliver B.,
Stove Christophe P.,
McKenzie Craig
Publication year - 2021
Publication title -
drug testing and analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 54
eISSN - 1942-7611
pISSN - 1942-7603
DOI - 10.1002/dta.2965
Subject(s) - cannabinoid receptor agonists , cannabinoid , enantiomer , potency , cannabinoid receptor , chemistry , synthetic cannabinoids , receptor , pharmacology , bioassay , in vitro , stereochemistry , antagonist , medicine , biology , biochemistry , genetics
Synthetic cannabinoid receptor agonists (SCRAs) elicit many of their psychoactive effects via type‐1 human cannabinoid (CB 1 ) receptors. Enantiomer pairs of eight tert ‐leucinate or valinate indole‐ and indazole‐3‐carboxamide SCRAs were synthesized and their CB 1 potency and efficacy assessed using an in vitro β‐arrestin recruitment assay in a HEK239T stable cell system. A chiral high‐performance liquid chromatography method with photodiode array and/or quadrupole time‐of‐flight‐mass spectrometry detection (HPLC‐PDA and HPLC‐PDA‐QToF‐MS) was applied to 177 SCRA‐infused paper samples seized in Scottish prisons between 2018 and 2020. In most samples, SCRAs were almost enantiopure ( S )‐enantiomer (>98% of total chromatographic peak area), although in some ( n = 18), 2% to 16% of the ( R )‐enantiomer was detected. ( S )‐enantiomers are consistently more potent than ( R )‐enantiomers and often more efficacious. The importance of SCRA‐CB 1 receptor interactions in the “head” or “linked group” moiety is demonstrated, with the conformation of the “bulky” tert ‐leucinate group greatly affecting potency (by up to a factor of 374), significantly greater than the difference observed between valinate SCRA enantiomers. ( S )‐MDMB‐4en‐PINACA, ( S )‐4F‐MDMB‐BINACA, and ( S )‐5F‐MDMB‐PICA are currently the most prevalent SCRAs in Scottish prisons, and all have similar high potency (EC 50 , 1–5 nM) and efficacy. Infused paper samples were compared using estimated intrinsic efficacy at the CB 1 receptor (EIE CB1 ) to evaluate samples with variable SCRA content. Given their similar potency and efficacy, any variation in CB 1 receptor‐mediated psychoactive effects are likely to derive from variation in dose, mode of use, pharmacokinetic differences, and individual factors affecting the user, rather than differences in the specific SCRA present.