Design, synthesis, and biological evaluation of arylpiperazine–benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory activities
作者:Suresh Paudel、Srijan Acharya、Kyeong-Man Kim、Seung Hoon Cheon
DOI:10.1016/j.bmc.2016.03.044
日期:2016.5
The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine–benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated
既定的5-羟色胺(5-羟色胺,5-HT)和去甲肾上腺素(NE)再摄取抑制剂的局限性需要开发更安全,更有效的治疗剂。根据4-苄基哌啶羧酰胺和曲唑酮的结构,设计,合成和评估化学支架与市售药物不同的芳基哌嗪-苄基哌啶,并评估其对神经递质再摄取的抑制活性。大多数合成化合物显示出比5-HT再摄取抑制更大的NE。其活性甚至大于标准药物盐酸文拉法辛。具有三碳连接基的衍生物表现出比具有二碳连接基的衍生物更好的活性。在新合成的化合物中,第2d表现出最强的神经递质再摄取抑制作用( NE的IC 50 = 0.38μM,5-HT的IC 50 = 1.18μM)。生物学活性数据表明,芳基哌嗪-苄基哌啶具有开发作为治疗神经精神病和神经退行性疾病的新型治疗剂的潜力。