Zhou Fenghua, Shi Yan, Tan Sujun, Wang Xiaoli, Yuan Weicheng, Tao Shuqi, Xiang Ping, Cong Bin, Ma Chunling, Wen Di
College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR China; Clinical Pathology Department, Shandong Second Medical University, Shandong Province, Weifang, Shandong Province 261042, PR China.
Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Science Platform, Key Laboratory of Judicial Expertise, Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai 200063, PR China.
Ecotoxicol Environ Saf. 2025 Jan 1;289:117500. doi: 10.1016/j.ecoenv.2024.117500. Epub 2024 Dec 10.
Due to the structural diversity and rapid prevalence of synthetic cannabinoids (SCs) in the market, the information linking the chemical structure of SCs to their toxicity remains scant, despite emerging in the 1970s. In the present study, we aimed to investigate the toxicity and underlying mechanisms of indole SCs JWH-018 and JWH-019 in mice (C57BL/6, male, 6-8 weeks old), zebrafish (AB strain, male, 4-5 months old) and modified human embryonic kidney (HEK) 293 T cells, using behavioral, pharmacokinetic, pharmacological approaches, and molecular docking. JWH-018 induced time- and dose-dependent cannabinoid-like effects in mice (administration dosages: 0.02, 0.1, and 0.5 mg/kg, i.p.), and yielded dose-dependent anxiogenic effects and lower aggression behavior in zebrafish (administration dosages: 0.01, 0.05, and 0.25 µg/g, i.p.), unlike JWH-019. These effects were blocked by the selective cannabinoid receptor 1 (CB1R) antagonist AM251. JWH-018, but not JWH-019, activated the CB1R-dependent extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway in vivo and in vitro. Molecular docking identified essential residues PHE, PHE, and TRP within CB1R as pivotal contributors to enhancing receptor-ligand associations. While both drugs had a similar binding pattern with shared linker binding pockets in CB1R, there were still differences in their spatial conformation. These findings shed light on the molecular pharmacology and activation mechanism of SCs for CB1R and should guide further research into the mechanisms underlying their deleterious effects in humans.
由于合成大麻素（SCs）在市场上结构多样且迅速流行，尽管其在20世纪70年代就已出现，但将SCs的化学结构与其毒性联系起来的信息仍然匮乏。在本研究中，我们旨在使用行为学、药代动力学、药理学方法以及分子对接技术，研究吲哚类SCs JWH - 018和JWH - 019对小鼠（C57BL/6，雄性，6 - 8周龄）、斑马鱼（AB品系，雄性，4 - 5月龄）和经修饰的人胚肾（HEK）293 T细胞的毒性及潜在机制。JWH - 018在小鼠中（腹腔注射剂量：0.02、0.1和0.5 mg/kg）诱导出时间和剂量依赖性的大麻素样效应，并且在斑马鱼中（腹腔注射剂量：0.01、0.05和0.25 μg/g）产生剂量依赖性的致焦虑效应和较低的攻击行为，这与JWH - 019不同。这些效应被选择性大麻素受体1（CB1R）拮抗剂AM251阻断。JWH - 018而非JWH - 019在体内和体外激活了CB1R依赖性细胞外信号调节激酶1和2（ERK1/2）通路。分子对接确定了CB1R内的关键残基苯丙氨酸、苯丙氨酸和色氨酸是增强受体 - 配体结合的关键因素。虽然两种药物在CB1R中具有相似的结合模式和共享的连接子结合口袋，但它们的空间构象仍存在差异。这些发现揭示了SCs对CB1R的分子药理学和激活机制，应为进一步研究其对人类有害作用的潜在机制提供指导。
