κ-阿片受体激动剂U50 488H的季胺化改造

王倩梅; 贾 敏; 冯 娜; 张淑苗; 李 娟; 樊 荣; 王跃民; 裴建明

κ-阿片受体激动剂U50 488H的季胺化改造

Structural transformation of κ-opioid receptor agonist (U50 488H) to quaternary ammonium salt

摘要

摘要: 目的:通过对κ-阿片受体激动剂U50 488H的结构进行季胺化改造，使其不能通过血脑屏障，从而消除可能存在的成瘾和依赖性。方法：对U50 488H进行季胺化改造，使用质谱法确认该季胺化产物，使用高效液相色谱法对比测定U50 488H及改造后的季胺化U50 488H在血清和脑中的浓度。结果：季胺化后的U50 488H呈淡黄色粉末样，经质谱分析，确认所得产物为U50 488H的碘甲烷季铵盐C20H29Cl2IN2O。后者溶解度较U50 488H明显增大。分别静脉注射U50 488H或季胺化U50 488H后，经色谱分析在血清中均可检测到所注射的药物；而在脑组织液中可以检测到U50 488H，却检测不到季胺化U50 488H。结论：成功改造获得一种新的化合物季胺化U50 488H，该物质不能通过血脑屏障，可以避免因U50 488H通过血液循环进入脑组织引起的成瘾和依赖性。

Abstract: AIM:To reduce the potential addiction of U50 488H, a κ-opioid receptor agonist, by structurally transforming it to its quaternary ammonium salt incapable of going through the blood-brain barrier. METHODS: U50 488H was transformed to its quaternary ammonium salt, which was identified with mass spectrometry. The concentrations of U50 488H and its quaternary ammonium salt in serum and brain tissue were determined by chromatography. RESULTS: The quaternary ammonium salt of U50 488H was a faint yellow powder and mass spectrometry proved it to be C20H29Cl2IN2O, with remarkably increased solubility than U50 488H. Chromatography detected U50 488H in both serum and brain tissue fluid of the rats after i.v. injection. However, quaternary ammonium salt of U50 488H was detected only in serum and not in brain tissue. CONCLUSION: The structural transformation of U50 488H to its quaternary ammonium salt incapable of going through the blood-brain barrier reduces the potential addiction of U50 488H.

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