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目的以5-羟色胺转运体和5-HT2A受体为靶点,设计合成N-吲哚烷基哌啶类化合物及其类似物,研究它们的体内外生物活性。方法以苯并五元氮杂化合物为原料,经烷基化反应,再与相应的哌啶或哌嗪类化合物进行缩合制备系列化合物。经5-羟色胺再摄取抑制实验和5-HT2A受体结合实验进行体外筛选,采用小鼠醋酸扭体法和小鼠热板法对其中优选化合物10c、10e进行体内镇痛活性实验;通过阿片受体结合试验和小鼠急性毒性试验,考察目标化合物作为新型非阿片类镇痛剂的潜在开发价值。结果与结论共合成了18个未见文献报道的新化合物,经高分辨质谱及核磁共振氢谱确证结构。体内外药理研究表明:化合物10c和10e具有较强的5-羟色胺再摄取抑制作用,且与5-HT2A受体有较高亲和力;10c、10e在两种镇痛模型上均显示出很强的镇痛活性,与阿片μ、δ、κ受体无明显亲和力,毒性较小,具有作为非阿片类新型镇痛剂的开发价值。
OBJECTIVE To design and synthesize N-indole alkylpiperidines and their analogs with serotonin transporters and 5-HT2A receptors as targets, and to study their in vitro and in vivo biological activities. Methods A series of compounds were prepared by the condensation of benzophenone aza compounds with the corresponding piperidine or piperazine compounds via alkylation. In vitro serotonin reuptake inhibition test and 5-HT2A receptor binding assay were performed in vitro, and the preferred compounds 10c and 10e were tested for their analgesic activities in vivo using mouse acetic acid writhing method and mouse hot plate method. Body binding assay and acute toxicity test in mice to investigate the potential value of the target compound as a novel non-opioid analgesic. RESULTS AND CONCLUSIONS A total of 18 new compounds were reported, which were confirmed by high-resolution mass and 1H-NMR. In vitro and in vivo pharmacological studies show that: Compounds 10c and 10e have a strong inhibition of serotonin reuptake and 5-HT2A receptors with higher affinity; 10c, 10e in both analgesic models showed a strong Analgesic activity, with opiate μ, δ, κ receptor no apparent affinity, less toxicity, as a new non-opioid analgesics development value.