σ_(1)和μ受体双靶点新型镇痛小分子的研究  

Study on dual-target novel analgesic small molecules based onσ_(1) receptor andμreceptor

作　　者：陈靖宇 杨俊[2] 黄俊龙 齐庆蓉[1] CHEN Jingyu;YANG Jun;HUANG Junlong;QI Qingrong(West China School of Pharmacy,Sichuan University,Chengdu,Sichuan,610041 P.R.China;West China Hospital,Sichuan University,Chengdu,Sichuan,610041 P.R.China)

机构地区：[1]四川大学华西药学院,四川成都610041 [2]四川大学华西医院,四川成都610041

出　　处：《华西药学杂志》2024年第1期7-12,共6页West China Journal of Pharmaceutical Sciences

摘　　要：目的设计并合成σ_(1)和μ受体双靶点小分子化合物,初步考察其对大鼠慢性坐骨神经缩窄(CCI)的镇痛效果。方法以间位被取代的溴苯为原料,经过C-N偶联、还原胺化反应制得目标化合物Ⅰa~Ⅰc。将110只SD大鼠随机均分为11组(空白对照组、阳性对照组、9个实验组),分别于左后肢制作CCI模型。术后7 d用二甲基亚砜处理空白对照组,用双氯芬酸钠处理阳性对照组,分别用低、中、高剂量的目标化合物Ⅰa~Ⅰc处理实验组。于给药前、后各时间点测量并比较各组大鼠的机械性痛阈,分析不同结构和剂量目标化合物对镇痛效果的影响。结果与结论合成了目标化合物Ⅰa~Ⅰc,并通过NMR、ESI-MS确证了结构。与给药前比较,二甲基亚砜对大鼠的机械性痛阈无显著影响,而实验组的机械性痛阈均有所升高,随着给药剂量的增大,镇痛效果也增强,但超过一定限度时镇痛效果增强不明显。化合物Ⅰa、Ⅰb分别于中、低剂量条件下显示出较Ⅰc更好的镇痛活性,为进一步改造双靶点神经镇痛药物提供了依据。OBJECTIVE To design and synthesize a series of small molecule compounds with dualσ_(1) andμreceptor interactions and to preliminarily investigate the neuropathic analgesic activities of different doses of these compounds on chronic sciatic nerve constriction(CCI)in rats.METHODS The target compoundsⅠa-Ⅰc were prepared from bromo-benzene substituted by different groups through C-N coupling reaction and reduction amination reaction.110 rats were randomly divided into 11 groups(blank control group,positive control group,9 experimental groups).Each group consists of 10 rats.CCI model was prepared on the left hind leg.7 days after operation,the blank control group was treated with DMSO,the positive control group was treated with diclofenac sodium,and the experimental group were treated with different doses of target compounds,respectively.The paw withdrawal threshold was measured and compared at different time points before and after administration.RESULTS and CONCLUSION The target compoundsⅠa-Ⅰc were synthesized.Their structures were confirmed by NMR and ESI-MS.Compared with before administration,DMSO had no significant effect on the mechanical pain threshold of rats,while the mechanical pain threshold was increased in the experimental groups with different doses.The analgesic effect may be enhanced with the increase of the dosage,but this effect may be not obvious when the dose exceeds a certain limit.CompoundsⅠa andⅠb showed better analgesic activity thanⅠc at medium and low doses,respectively,which provided a basis for further modification of dual-target analgesic drugs for neuropathic pain.

关 键 词：神经病理性疼痛 σ_(1)受体 Μ受体 双靶点 大鼠慢性坐骨神经缩窄损伤 双氯芬酸钠 镇痛 机械缩爪阈值 小分子 合成 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]