Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L-valine or L-tert-leucine.
Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L-valine or L-tert-leucine.
复制标题
以 L-缬氨酸或 L-叔亮氨酸为支架的合成大麻素受体激动剂的羧基代谢物的功能评估。
DOI：
10.1002/dta.2607
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发表时间：
2019
影响因子：
2.9
通讯作者：
C. Stove
中科院分区：
文献类型：
--
作者：
Elise Wouters;Lukas Mogler;Annelies Cannaert;V. Auwärter;C. Stove
基于吲哚和吲唑的合成大麻素受体激动剂（SCRAs），具有缬氨酸或叔亮氨酸取代基，是常被滥用的新精神活性物质（NXP）。这些SCRA的主要代谢途径是末端酰胺或甲酯官能团的水解。虽然这些水解产物已被检测为某些“法律的兴奋剂”的主要成分，但这些代谢产物的特征往往很差。在这里，我们报告了一个系统的研究活动的7个常见的水解代谢产物的15个SCRA具有支架的基础上L-缬氨酸或L-叔亮氨酸直接比较其母体化合物。使用基于活性的大麻素受体1（CB 1）生物测定法在稳定的HEK 293 T细胞系统中分析SCRA及其代谢产物的活性。通过添加（推定的）SCRAs引起β-抑制蛋白2向活化的CB 1（各自融合至分裂的纳米荧光素酶的一部分）的募集。通过96孔板读数器监测功能互补的荧光素酶的发光。5 F-AB-PINACA、ADB-CHMICA、ADB-CHMINACA、ADB-FUBICA及其甲酯和乙酯衍生物的主要水解代谢产物在浓度高达1 μM时未显示出可检测的CB 1活化。另一方面，5 F-ADB-PINACA、AB-CHMINACA和ADB-FUBINACA的代谢物保留了活性，尽管与母体化合物相比显著降低（EC 50值>100 nM）。基于活性的表征SCRA及其代谢物在CB 1不仅可以更好地了解SCRA及其代谢物在中毒中的复杂相互作用，而且还可以允许应用存在于生物液体或没收材料中的“活性当量”概念。
Indole- and indazole-based synthetic cannabinoid receptor agonists (SCRAs), featuring valine or tert-leucine substituents, are commonly abused new psychoactive substances (NPS). A major metabolic pathway for these SCRAs is hydrolysis of the terminal amide or methylester functionalities. Although these hydrolysis products were already detected as main ingredients in some "legal highs," these metabolites are often poorly characterized. Here, we report a systematic investigation of the activity of 7 common hydrolysis metabolites of 15 SCRAs featuring scaffolds based on L-valine or L-tert-leucine in direct comparison to their parent compounds. An activity-based cannabinoid receptor 1 (CB1 ) bio-assay was used for activity profiling of SCRAs and their metabolites in a stable HEK293T cell system. The recruitment of β-arrestin2 to the activated CB1 (each fused to one part of a split Nanoluciferase) was provoked by adding the (putative) SCRAs. Luminescence of the functionally complemented luciferase was monitored by a 96-well plate-reader. The major hydrolysis metabolites of 5F-AB-PINACA, ADB-CHMICA, ADB-CHMINACA, ADB-FUBICA, and their methyl- and ethylester derivatives showed no detectable CB1 activation at concentrations up to 1 μM. On the other hand, metabolites of 5F-ADB-PINACA, AB-CHMINACA, and ADB-FUBINACA did retain activity, although significantly reduced as compared to the parent compounds (EC50 values >100 nM). Activity-based characterization of SCRAs and their metabolites at CB1 may not only allow a better insight into the complex interplay between SCRAs and their metabolites in intoxications, but may also allow application of the concept of "activity equivalents" present in biological fluids or, alternatively, in confiscated materials.
影响因子：
2.9
作者：
Franz, Florian;Angerer, Verena;Auwaerter, Volker
通讯作者：
Auwaerter, Volker
影响因子：
5.8
作者：
Brents LK;Gallus-Zawada A;Radominska-Pandya A;Vasiljevik T;Prisinzano TE;Fantegrossi WE;Moran JH;Prather PL
通讯作者：
Prather PL