N-吲哚烷基哌啶类化合物及其类似物的合成和活性研究

Synthesis and biological activities of N-indolalkyl piperidine derivatives and their analogues

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。

Aim According to the targets of 5-HT transporter and 5-HT2A receptor, a series of N-indolalkyl piperidine derivatives and their analogues were synthesized and tested for their biological activities. Methods Eighteen compounds were prepared from benzo-fused nitrogen heterocycles through N-alkylation and then condensation with derivatives of piperidine or piperazine. All of them were carried out in vitro pharmacological test for the 5-HT transporter and 5-HT2A receptor. Among the tested compounds 10c and 10e were trialed analgesic activities in both mice writhing and mice hot plate models. Results and conclusion Eighteen novel compounds were prepared, and their structures were confirmed by ^1H-NMR and HRMS. Most of them showed high affinity for the 5-HT transporter and 5-HT2A receptor. 10c and 10e exhibited potent analgesic activities in two models in vivo with low affinity to μ, δ, κ receptors, which is a chance to find a better precursor of non-opioid analgesic for further optimization.