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
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
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DOI：
10.1002/dta.2965
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发表时间：
2020-12-09
影响因子：
2.9
通讯作者：
McKenzie, Craig
中科院分区：
文献类型：
--
作者：
Antonides, Lysbeth H.;Cannaert, Annelies;McKenzie, Craig
合成大麻素受体激动剂 (SCRA) 通过 1 型人类大麻素 (CB1) 受体引发许多精神作用。合成了八个叔亮氨酸或缬氨酸吲哚-和吲唑-3-甲酰胺 SCRA 的对映体对，并在 HEK239T 稳定细胞系统中使用体外 β-抑制蛋白招募测定评估了它们的 CB1 效力和功效。采用光电二极管阵列和/或四极杆飞行时间质谱检测的手性高效液相色谱方法（HPLC-PDA 和 HPLC-PDA-QToF-MS）对 2018 年至 2020 年间在苏格兰监狱查获的 177 个 SCRA 注入纸样进行了分析。在大多数样品中，SCRA 几乎是对映体纯 (S)-对映体（占总色谱峰的 98% 以上）区域），尽管在一些（n = 18）中，检测到 2% 至 16% 的 (R)-对映异构体。 (S)-对映体始终比 (R)-对映体更有效，而且通常更有效。 SCRA-CB1 受体在“头部”或“连接基团”部分相互作用的重要性得到了证明，“庞大”的叔亮氨酸基团的构象极大地影响了效力（高达 374 倍），显着大于缬氨酸 SCRA 对映体之间观察到的差异。 (S)-MDMB-4en-PINACA、(S)-4F-MDMB-BINACA 和 (S)-5F-MDMB-PICA 是目前苏格兰监狱中最常见的 SCRA，并且都具有相似的高效力（EC50，1-5 nM）和功效。使用 CB1 受体 (EIECB1) 的估计内在功效对输注纸样品进行比较，以评估具有可变 SCRA 含量的样品。鉴于它们相似的效力和功效，CB1受体介导的精神作用的任何变化都可能源自剂量、使用方式、药代动力学差异和影响使用者的个体因素的变化，而不是具体 SCRA 存在的差异。
Synthetic cannabinoid receptor agonists (SCRAs) elicit many of their psychoactive effects via type-1 human cannabinoid (CB1) receptors. Enantiomer pairs of eight tert-leucinate or valinate indole- and indazole-3-carboxamide SCRAs were synthesized and their CB1 potency and efficacy assessed using an in vitro beta-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 were compared using estimated intrinsic efficacy at the CB1 receptor (EIECB1) to evaluate samples with variable SCRA content. Given their similar potency and efficacy, any variation in CB1 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.