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 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‐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 (EIE_CB1) 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.

中文翻译：

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形状问题：基于活性的体外生物测定和手性分析在监狱缉获的毒品纸中合成大麻素受体激动剂的药理学评价中的应用

合成大麻素受体激动剂 (SCRA) 通过 1 型人类大麻素 (CB ₁ ) 受体引起许多精神活性作用。合成了八个叔亮氨酸或缬氨酸吲哚和吲唑 3 甲酰胺 SCRA 的对映异构体对，并在 HEK239T 稳定细胞系统中使用体外β-抑制蛋白募集试验评估了它们的 CB ₁效力和功效。使用光电二极管阵列和/或四极杆飞行时间质谱检测（HPLC-PDA 和 HPLC-PDA-QToF-MS）的手性高效液相色谱方法对苏格兰监狱缉获的 177 份注入 SCRA 的纸样进行了应用2018 年至 2020 年之间。在大多数样本中，SCRA 几乎是对映体纯的（S)-对映异构体（> 98% 的总色谱峰面积），尽管在一些（n = 18）中，检测到2% 到 16% 的 ( R )-对映异构体。( S )-对映异构体始终比 ( R )-对映异构体更有效，并且通常更有效。证明了 SCRA-CB ₁受体相互作用在“头部”或“连接基团”部分的重要性，“庞大的”叔亮氨酸基团的构象极大地影响了效力（高达 374 倍），显着更大比在缬氨酸盐 SCRA 对映异构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流行的 SCRA，并且都具有相似的高效力 (EC ₅₀ , 1-5 nM) 和功效。使用估计的 CB ₁受体 (EIE _CB1 )内在功效比较灌注纸样品，以评估具有可变 SCRA 含量的样品。鉴于其相似的效力和功效，CB ₁受体介导的精神作用的任何变化都可能源于剂量、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，而不是存在的特定 SCRA 的差异。