Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples
Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples
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DOI：
10.3389/fchem.2019.00321
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发表时间：
2019-05-16
影响因子：
5.5
通讯作者：
McKenzie, Craig
中科院分区：
文献类型：
--
作者：
Antonides, Lysbeth H.;Cannaert, Annelies;McKenzie, Craig
多年来，合成大麻素受体激动剂一直是向国际监测和预警系统报告的最大一类非法精神活性物质。酰胺型SCRA是最普遍和最有效的。报道了4种吲唑-3-甲酰胺化合物AMB-FUBINACA、AB-FUBINACA、5 F-MDMB-PINACA（5 F-ADB）和AB-CHMINACA的对映选择性合成和表征。使用基于分裂NanoLuc荧光素酶的功能互补的G-蛋白偶联受体（GPCR）活化测定和测定的EC 50（效力的量度）和E-max（功效的量度）值研究化合物与CB 1和CB 2受体的相互作用。所有化合物对CB 2受体的效力均高于对CB 1受体的效力，并且（S）-对映异构体对两种受体的效力均高于（R）-对映异构体。对映体对CB 2受体的相对效力受结构特征的影响。具有胺部分的化合物（AB-FUBINACA和AB-CHMINACA）的差异比具有酯部分的化合物（AMB-FUBINACA和5 F-MDMB-PINACA）更明显。开发了一种高效液相色谱法，以确定缉获样品中（R）-对映体的普遍性。Lux（R）直链淀粉-1 [直链淀粉三（3，5-二甲基苯基氨基甲酸酯）]对具有末端甲酯部分的SCRA具有最大选择性，Lux（R）i-纤维素-5柱对具有末端酰胺部分的SCRA具有最大选择性。优化的等度分离方法得到对映体分离度值（Rs）>= 1.99。对缴获的草药材料进行非手性GC-MS分析（n = 16），发现5 F-MDMB-PINACA（
Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB1 and CB2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC50 (a measure of potency) and E-max (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB2 receptor than at the CB1 receptor and (S)-enantiomers had an enhanced potency to both receptors over the (R)-enantiomers. The relative potency of the enantiomers to the CB2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of (R)-enantiomers in seized samples. Lux (R) Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux (R) i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) >= 1.99. Achiral GC-MS analysis of seized herbal materials (n = 16), found 5F-MDMB-PINACA (