新型哌啶芳酰胺类镇痛小分子的合成及初步活性评价

Synthesis and preliminary biological evaluation of novel piperidine arylamide analgesic small molecules

目的设计并合成一系列新型镇痛小分子,初步考察目标化合物对大鼠慢性坐骨神经缩窄(CCI)的镇痛效果。方法基于σ_(1)和μ受体双靶点镇痛活性化合物Ⅶ的结构改造,以不同基团取代的苯胺为原料,通过Wittig-Horner、氢化还原、羰基还原、亲核取代等反应得到目标产物Ⅰ。建立CCI疼痛模型,分别于给药前、后各时间点测量并比较各组大鼠的机械性痛阈,初步分析不同结构对镇痛效果的影响。结果与结论合成了3个目标化合物Ⅰ,并用NMR、ESI-MS确证了结构。与给药前比较,空白组大鼠的机械性痛阈无显著影响,而实验组及对照组大鼠的机械性痛阈均有提升;与对照组比较,各实验组大鼠的镇痛效果无明显差异;与空白组比较,差异有统计学意义。

OBJECTIVE To design and synthesize a series of novel small analgesic molecules and to preliminarily investigate their analgesic efficacy on chronic sciatic nerve constriction(CCI)in rats.METHODS Based on the structural modification of compound V,a dual-target analgesic agent acting on σ_(1) andμ receptors,target products I were synthesized from substituting different aromatic amines by the Wittig-Horner reaction,hydrogenation reduction reaction,carbonyl reduction reaction,and nucleophilic substitution reaction.A CCI rat model was establisted to analyze the analgesic properties of different compound structures.The mechanical pain thresholds of the rats were measured and compared before and after drug administration.RESULTS and CONCLUSION The three target compounds I were synthesized,with their structures confirmed by NMR and ESI-MS.After-administration,the saline group showed no significant change in the mechanical pain threshold.In contrast,the experimental and positive control groups demonstrated an increase in the mechanical pain threshold of the rats.The analgesic effects of the experimental groups were not significantly different from those of the gabapentin group,indicating comparable efficacy.However,significant differences were observed when compared to the saline group,underscoring the potential of these compounds as effective analgesics.