基于中缝背核nNOS-SERT蛋白偶联快速起效抗抑郁靶点及小分子新药研究

五羟色胺(5-HT)转运子(SERT)抑制剂(SSRIs)抑制5-HT能神经元轴突末梢突触前膜的SERT发挥抗抑郁作用；但同时抑制中缝背核(DRN)体树突区SERT，激活5-HT1A自身受体(5-HT1AAutoR)发挥负反馈作用，抑制5-HT能神经元放电，阻碍SSRIs发挥作用。待5-HT1AAutoR脱敏后，SSRIs发挥抗抑郁疗效。DRN区5-HT1AAutoR脱敏稳定性是SSRIs延迟起效、不稳定等副作用的根源。本项目提出新假说：DRN区特异性存在的神经元型一氧化氮合酶(nNOS)-SERT偶联增加，导致体树突区SERT内吞，DRN区细胞间隙5-HT增加，激活5-HT1AAutoR，抑制5-HT能神经元放电诱发抑郁；设计合成小分子药物解开nNOS-SERT偶联，抑制DRN区5-HT/5-HT1AAutoR通路，不依赖于其脱敏，具有快速抗抑郁，稳定、效果强等诸多优点，革新了单胺理论。

Selective serotonin reuptake inhibitors (SSRIs) inhibits serotonin transporter (SERT) in presynaptic membrane of axon terminals of 5-HT neurons to elicit antidepressantive effect. Meanwhile, SSRIs inhibits SERT on the somatodendrite region of serotoniergic neuron in the dorsal raphe nucleus (DRN), activates 5-HT1A autoreceptor (5-HT1AAutoR), and plays a negative feedback role. Thus, SSRIs inhibits neural firing of serotoniergic neurons, blocking the antidepressive effect of SSRIs treatment. After desensitization of 5-HT1AAutoR, SSRIs begins to show antidepressant effect. The desensitization stability of 5-HT1AAutoR in DRN region is the cause of side effects such as delayed onset and instability of SSRIs. This project proposes a new hypothesis: the increase of neuronal nitric oxide synthetase (nNOS) - SERT coupling in the DRN region leads to the endocytosis of SERT on the somatodendritic region, then increases the concentation of intercellular 5-HT in the DRN, activating 5-HT1AAutoR, reducing neural firing of serotoniergic neuron, and causing depressvie symptom; Small molecule drugs designed and synthetized based on uncoupling nNOS-SERT inhibits 5-HT/ 5-HT1AAutoR pathway, exerts rapidly onset, stable, and strong antidepressive effect independently of desensitization of 5-HT1AAutoR. Overall, this project will reveal a novel therapeutic target of depression and will develop a totally new type of antidepressant without side effects of SSRIs, bringing innovation of monoamine theory.