Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Willow Grove, PA, USA.
Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Drug Test Anal. 2021 Feb;13(2):427-438. doi: 10.1002/dta.2935. Epub 2020 Oct 5.
A new class of synthetic cannabinoids has emerged as new psychoactive substances (NPS). Similar in structure to JWH-022, these substances contain alkene modifications to the tail region of the synthetic cannabinoid core structure, and nomenclature denotes these new analogues as pent-4en or but-3en species. Internationally, two analogues from this new series recently emerged: MDMB-4en-PINACA and MMB-4en-PICA. Previously, data regarding activity and potential toxicity were not available. In vitro assessment of cannabinoid receptor 1 (CB1) activation via the β-arrestin 2 recruitment was studied for three (3) pent-4en analogues, one (1) but-3en analogue, and one (1) principal metabolite. MDMB-4en-PINACA (2.47 nM, 239%), MDMB-4en-PICA (11.5 nM, 302%), and MDMB-3en-BINACA (14.3 nM, 286%) were highly potent and efficacious (comparison: JWH-018, 25.3 nM, 100%), while the potencies of MMB-4en-PICA and MDMB-4en-PINACA 3,3-dimethylbutanoic acid were markedly lower. Modifications to core and tail structural features (i.e., indole vs. indazole) led to relatively small differences in potency, while changes among the head region led to larger differences. Sample-mining and data-mining conducted on toxicology samples led to the identification of MDMB-4en-PINACA in 25 forensic toxicology cases, including postmortem and impaired driving investigations, with case details and limited histories described herein. Moderate geographical distribution of MDMB-4en-PINACA was noted in the United States with emergence in the Northeast, Midwest, South, and West regions. Results from toxicology testing paired with case history show the potential for MDMB-4en-PINACA to cause or contribute to impairment or death. Forensic scientists, public health and public safety officials, law enforcement, clinicians, medical examiners, and coroners should consider involvement of emergent synthetic cannabinoids in their work and that new analogues containing an alkene tail can retain similar or increased potency and toxicity.
一类新的合成大麻素已作为新型精神活性物质（NPS）出现。这些物质在结构上与 JWH-022 相似，在合成大麻素核心结构的尾部区域含有烯烃修饰，命名法将这些新类似物表示为戊-4-烯或丁-3-烯。在国际上，这个新系列最近出现了两种类似物：MDMB-4en-PINACA 和 MMB-4en-PICA。此前，关于这些物质的活性和潜在毒性的数据尚不可用。通过β-arrestin 2 募集来评估大麻素受体 1（CB1）激活的体外评估，研究了三种（3）戊-4-烯类似物、一种（1）丁-3-烯类似物和一种（1）主要代谢物。MDMB-4en-PINACA（2.47 nM，239%）、MDMB-4en-PICA（11.5 nM，302%）和 MDMB-3en-BINACA（14.3 nM，286%）具有高活性和高效性（比较：JWH-018，25.3 nM，100%），而 MMB-4en-PICA 和 MDMB-4en-PINACA 3,3-二甲基丁酸的效力明显较低。核心和尾部结构特征的修饰（即吲哚与吲哚唑）导致效力差异相对较小，而头部区域的变化导致较大差异。对毒理学样本进行的样本挖掘和数据挖掘导致在 25 例法医毒理学案例中鉴定出 MDMB-4en-PINACA，包括死后和驾驶能力受损调查，本文描述了案例详情和有限的病史。在美国，MDMB-4en-PINACA 的分布范围较广，在东北部、中西部、南部和西部都有出现。毒理学测试结果与案例史相结合表明，MDMB-4en-PINACA 有可能导致或促成损伤或死亡。法医科学家、公共卫生和公共安全官员、执法人员、临床医生、法医和验尸官应考虑将新出现的合成大麻素纳入其工作范围，并且含有烯烃尾部的新类似物可以保留相似或增加的效力和毒性。
