Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of "Nitazene" 2-Benzylbenzimidazole Synthetic Opioids
Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of "Nitazene" 2-Benzylbenzimidazole Synthetic Opioids
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DOI：
10.1021/acschemneuro.1c00064
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发表时间：
2021-03-24
影响因子：
5
通讯作者：
Stove, Christophe P.
中科院分区：
文献类型：
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作者：
Vandeputte, Marthe M.;Van Uytfanghe, Katleen;Stove, Christophe P.
最近在非法市场上出现了几种2-苄基苯并咪唑类阿片（也称为“硝氮类”）。最常遇到的成员是isotonitazene，自2019年出现以来，已在多起死亡事件中被确定。虽然最近的列表努力针对isotonitazene，但许多其他类似物仍然不受管制。由于在结构上与芬太尼无关，因此对这些化合物的潜在危害知之甚少。在本研究中，合成了10种硝唑和4种代谢物，通过4种不同的技术进行了分析表征，并使用两种基于细胞的β-抑制蛋白2/mini-Gi募集试验监测μ-阿片受体（莫尔）活化进行了评价。基于吸收光谱和保留时间，高效液相色谱法结合二极管阵列检测（HPLC-DAD）允许区分大多数类似物。飞行时间质谱（LC-QTOF-MS）鉴定了12/14个化合物的m/z为100.11的片段，这可以作为基于MS筛选硝氮烯的基础。莫尔比活性测定证实，硝氮类化合物通常具有高活性，几种类似物的效力和功效超过芬太尼。特别相关的是，N-去乙基异烟酸代谢物的效力出乎意料地非常高，与依托烟酸的效力相当，并超过异烟酸本身的效力。通过其在死亡中的鉴定，这可能具有体内后果。这些结果通过为阿片类药物的检测提供一个分析框架，以及为它们的莫尔激活潜力提供重要的新见解，提高了我们对这一新兴阿片类药物的理解。
Several 2-benzylbenzimidazole opioids (also referred to as "nitazenes") recently emerged on the illicit market. The most frequently encountered member, isotonitazene, has been identified in multiple fatalities since its appearance in 2019. Although recent scheduling efforts targeted isotonitazene, many other analogues remain unregulated. Being structurally unrelated to fentanyl, little is known about the harm potential of these compounds. In this study, ten nitazenes and four metabolites were synthesized, analytically characterized via four different techniques, and pharmacologically evaluated using two cell-based beta-arrestin2/mini-Gi recruitment assays monitoring mu-opioid receptor (MOR) activation. On the basis of absorption spectra and retention times, high-performance liquid chromatography coupled to diode-array detection (HPLC-DAD) allowed differentiation between most analogues. Time-of-flight mass spectrometry (LC-QTOF-MS) identified a fragment with m/z 100.11 for 12/14 compounds, which could serve as a basis for MS-based nitazene screening. MOR activity determination confirmed that nitazenes are generally highly active, with potencies and efficacies of several analogues exceeding that of fentanyl. Particularly relevant is the unexpected very high potency of the N-desethylisotonitazene metabolite, rivaling the potency of etonitazene and exceeding that of isotonitazene itself. Supported by its identification in fatalities, this likely has in vivo consequences. These results improve our understanding of this emerging group of opioids by laying out an analytical framework for their detection, as well as providing important new insights into their MOR activation potential.