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

AbstractSynthetic cannabinoid receptor agonists (SCRAs) elicit many of their psychoactive effects via type ‐1 human cannabinoid (CB1) receptors. Enantiomer pairs of eighttert‐leucinate or valinate indole‐ and indazole‐3‐carboxamide SCRAs were synthesized and their CB1 potency and efficacy assessed using anin vitroβ‐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‐CB1 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 (EC50, 1 ‐5 nM) and efficacy. Infused paper samples w...

Source: Drug Testing and Analysis - November 8, 2020 Category: Drugs & Pharmacology Authors: Lysbeth H. Antonides, Annelies Cannaert, Caitlyn Norman, Niamh Nic Daeid, Oliver B. Sutcliffe, Christophe P. Stove, Craig McKenzie Tags: RESEARCH ARTICLE Source Type: research