Qin Youfa, Huang Yihan, Ji Xiaolan, Gong Ling, Luo Shiqiong, Gao Jiapan, Liu Rui, Zhang Tao
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, China.
Front Pharmacol. 2024 Jul 31;15:1389761. doi: 10.3389/fphar.2024.1389761. eCollection 2024.
Sinomenine hydrochloride (SH) is commonly used in the treatment of rheumatoid arthritis. It activates mast cells and induces anaphylaxis in the clinical setting. Adverse drug reactions can be caused by activation of MAS-associated G protein-coupled receptor X2 (MRGPRX2) on mast cells. Because the ligand binding site of MRGPRX2 is easily contacted in dilute solvents, it can be activated by many opioid drug structures. N-Demethylsinomenine (M-3) has a similar chemical structure to that of the opioid scaffold and is a major metabolite of SH. We sought to clarify whether M-3 induces anaphylaxis synergistically with its prototype in a mouse model. Molecular docking computer simulations suggested a similar binding effect between M-3 and SH. M-3 was chemically synthesized and analyzed by surface plasmon resonance to reveal its affinity for MRGPRX2. Temperature monitoring, hindlimb swelling and exudation test, and mast cell degranulation test were used to explore the mechanism of MRGPrx2 mediated allergic reaction triggered by M-3. Reduced M-3-induced inflammation was evident in MrgprB2 (the ortholog of MRGPRX2) conditional (Cpa3-Cre/MrgprB2flox) knockout (MrgprB2-CKO) mice. Additionally, LAD2 human mast cells with MRGPRX2 knockdown showed reduced degranulation. M-3 activated LAD2 cells synergistically with SH as regulated by GRK2 signaling and IP3R/PLC/PKC/P38 molecular signaling pathways. The results indicate that the M-3 metabolite can activate mast cells synergistically with its prototype SH via MRGPRX2 and aggravate anaphylaxis. These findings provide important insights into drug safety.
盐酸青藤碱（SH）常用于治疗类风湿性关节炎。在临床环境中，它会激活肥大细胞并引发过敏反应。药物不良反应可能由肥大细胞上的MAS相关G蛋白偶联受体X2（MRGPRX2）激活所致。由于MRGPRX2的配体结合位点在稀溶液中易于接触，它可被许多阿片类药物结构激活。去甲青藤碱（M-3）与阿片类药物骨架具有相似的化学结构，是SH的主要代谢产物。我们试图在小鼠模型中阐明M-3是否与其原型协同诱导过敏反应。分子对接计算机模拟表明M-3和SH之间具有相似的结合效应。通过化学合成M-3并利用表面等离子体共振进行分析，以揭示其对MRGPRX2的亲和力。采用温度监测、后肢肿胀和渗出试验以及肥大细胞脱颗粒试验，以探究MRGPrx2介导的由M-3引发的过敏反应机制。在MrgprB2（MRGPRX2的直系同源物）条件性（Cpa3-Cre/MrgprB2flox）敲除（MrgprB2-CKO）小鼠中，M-3诱导的炎症明显减轻。此外，MRGPRX2敲低的LAD2人肥大细胞脱颗粒减少。M-3与SH协同激活LAD2细胞，受GRK2信号传导和IP3R/PLC/PKC/P38分子信号通路调控。结果表明，M-3代谢产物可通过MRGPRX2与其原型SH协同激活肥大细胞并加重过敏反应。这些发现为药物安全性提供了重要见解。
