新型5-HT/NA/DA三重再摄取抑制剂作为高效低毒抗抑郁活性分子研究

Recent research showed that triple reuptake inhibitors are promising chemical entities for the treatment of depression. It is believed that the triple reuptake inhibitors have better efficacy and fewer side effects compared with traditional antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs). We have disclosed a series of aralkyl diamine compounds in our previous investigation, which showed potent inhibition of the 5-HT, NA and DA transporters in vitro and antidepressant activity in vivo. However, high levels inhibition of DA compared to 5-HT and NA may increase side effect. Based on these results, 50-60 new aralkyl diamine compounds will be designed and synthesized. We will investigate their antidepressant activities in vitro and in vivo. Further, It is of interesting to characterize the in vivo pharmacology of these compounds in microdialysis studies, which can determine the effects on extracellular concentrations of monoamines. Then the influence of these new compounds on locomotor activity and stereotyped behavior will be evaluated. Thus it is conceivable that we can shed light on the relationship of the side effects and the ratios of inhibition of 5-HT, NA and DA reuptake transporters and figure out the suitable DA strength in the three monoamine transporters.

5-HT/NA/DA三靶点再摄取抑制剂是目前抗抑郁新药研究的重要发展方向，较之5-HT/NA双重再摄取抗抑郁药物具有提高有效性、缩短起效时间等优势。申请人前期发现了一类芳烷二胺类化合物，具有较强的5-HT/NA/DA三靶点再摄取抑制作用和较好的动物体内抗抑郁活性，但部分DA再摄取抑制作用较强的化合物显示了一定的毒副作用。本申请课题将在上述研究基础上，设计合成50-60个芳烷二胺类新化合物，对其体内外活性及毒副作用进行研究，并进行小鼠自发活动增强试验、小鼠刻板行为研究及大鼠脑组织5-HT/NA/DA含量的测定，探讨在5-HT/NA/DA三靶点作用中，DA再摄取抑制强度与化合物活性及毒副作用间关系。在进行化合物构效关系分析基础上，确定DA在5-HT/NA/DA三靶点作用中的合适强度范围，为发现高效低毒的芳烷二胺类多靶点抗抑郁新活性分子提供指导。

抑郁症是常见的精神疾病，具有慢性、易复发等特点。预计到2020年，抑郁症将成为危害人类健康的世界第二大疾病。目前临床使用的抗抑郁药物均存在副作用较大，起效迟缓，有效性差等缺点。因此，临床亟需新型抗抑郁药，以治疗日益增多的抑郁患者。5-HT/NA/DA 三重再摄取抑制剂与传统的抗抑郁药相比，具有起效快，有效性高等优势，是目前抗抑郁新药研究的重要发展方向。. 本课题设计、合成了60个新型芳烷二胺类三重再摄取抑制剂，通过对新化合物进行体内外活性及毒副作用等研究， 探讨DA 再摄取抑制强度与毒副作用间关系， 确定了DA 在 5-HT/NA/DA 三靶点作用中的合适强度范围，发现了新型多靶点抗抑郁新活性分子SIPI6116具有活性强，毒性低等特点，为设计合成新型多靶点抗抑郁化合物提供理论指导。. 本课题研究已申请中国发明专利2项，研究成果具有完全自主知识产权，并发表SCI论文3篇。本课题的研究成果具有重要的科学意义和和应用价值。