Division of Drug Research, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85, Linköping, Sweden.
Division of Drug Research, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85, Linköping, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, SE, 587 58 Linköping, Sweden.
Forensic Sci Int. 2020 Dec;317:110553. doi: 10.1016/j.forsciint.2020.110553. Epub 2020 Oct 23.
New psychoactive substances (NPS) appear on the recreational market on a monthly basis, with unclear toxicology, resulting in an increasing number of fatalities. Identification of drug targets and potencies is crucial for understanding and treating intoxications and for scheduling processes. In this study 60 NPS and metabolites belonging to opioids, cannabinoids and serotonergic hallucinogens classes were screened for in vitro activation of the μ-opioid, CB1, 5-HT and 5-HT receptors using the AequoZen cell system. Fentanyl and NBOMe analogues were chosen for full dose-response characterization of the μ-opioid and 5-HT receptors, respectively. Most substances activated their corresponding target receptor. The most potent μ-opioid receptor agonists were 2-fluorofentanyl (EC = 1.0 nM), carfentanil (EC = 2.7 nM) and acrylfentanyl (EC = 2.8 nM) and in total a >1500-fold difference was seen among the tested compounds. Moreover, furanylfentanyl, 4-methoxybutyrylfentanyl and valerylfentanyl acted as partial agonists of the μ-receptor. On the 5-HT receptor, bromo-dragonfly showed the highest potency (EC = 0.05 nM, 400 times more potent than LSD), followed by most NBOMe compounds with EC values ranging from 0.11 nM (for 25N-NBOMe) to 1.3 nM (for 25T4-NBOMe)). Off-target activation of the μ-opioid receptor was identified for piperazines, phenethylamines (in particular NBOMe and 2C compounds) and tryptamines. Moreover, the synthetic cannabinoid metabolite 3-carboxy indole PB-22 activated the 5-HT receptor. Bromo-dragonfly was the only compound that activated all four receptors. These results highlight the possible interplay of known and unknown NPS targets and unveil its complexity. Moreover, the detailed, quantitative information presented facilitates our further understanding of NPS toxicology.
新型精神活性物质（NPS）每月都会出现在娱乐市场上，其毒理学性质尚不清楚，导致中毒死亡人数不断增加。鉴定药物靶点和效力对于了解和治疗中毒以及进行调度程序至关重要。在这项研究中，使用 AequoZen 细胞系统筛选了属于阿片类、大麻素类和血清素致幻剂类的 60 种 NPS 和代谢物，以检测其对 μ-阿片类、CB1、5-HT 和 5-HT 受体的体外激活作用。选择芬太尼和 NBOME 类似物分别对 μ-阿片类和 5-HT 受体进行全面的剂量反应特征描述。大多数物质激活了其相应的靶受体。最有效的 μ-阿片类受体激动剂是 2-氟芬太尼（EC=1.0 nM）、卡芬太尼（EC=2.7 nM）和丙烯芬太尼（EC=2.8 nM），在测试的化合物中，其效力相差超过 1500 倍。此外，呋喃芬太尼、4-甲氧基丁酰芬太尼和戊酰芬太尼作为 μ 受体的部分激动剂。在 5-HT 受体上，溴龙蝇表现出最高的效力（EC=0.05 nM，比 LSD 高 400 倍），其次是大多数 NBOME 化合物，EC 值范围从 0.11 nM（25N-NBOME）到 1.3 nM（25T4-NBOME）。哌嗪类、苯乙胺类（特别是 NBOME 和 2C 类化合物）和色胺类化合物对 μ-阿片类受体的非靶标激活作用已被确定。此外，合成大麻素代谢物 3-羧基吲哚 PB-22 激活了 5-HT 受体。溴龙蝇是唯一激活所有四个受体的化合物。这些结果突出了已知和未知 NPS 靶点的可能相互作用，并揭示了其复杂性。此外，呈现的详细、定量信息有助于我们进一步了解 NPS 毒理学。
