新型抗抑郁剂ZY-1408快速起效的5-HT2C受体机制

Currently available antidepressants are administered for several weeks before producing therapeutic effects. We previously found that the novel compound ZY-1408 has antidepressant-like effects in animal models of depression and possesses high affinity for serotonin transporters, norepinephrine transporters, and serotonin 2C (5-HT2C) receptors. Similar to selective 5-HT2C antagonists, ZY-1408 exerts antidepressant actions with a faster rate of onset than that of currently used selective serotonin and norepinephrine reuptake inhibitor antidepressants, such as duloxetine. Moreover, we found that the 5-HT2C receptor agonist CP-809101 completely blocks the rapid-onset antidepressant-like effect of ZY-1408. The present project is based on these previous results and focuses on the contribution of the 5-HT2C receptor to the antidepressant effect of ZY-1408. We will investigate the pharmacological profile of ZY-1408 at different levels, including its receptor affinity profile and its ability to alter monoamine neurotransmitter concentrations, electrical activity of neurons and neuronal plasticity, using behavioral pharmacology, cell biology, electrophysiology, and molecular biology techniques. This project is expected to provide experimental evidence for use in developing independent intellectual property rights for ZY-1408. Importantly, it is expected that this project will provide new directions for the development of multi-target antidepressants with faster onsets of action.

目前抗抑郁药物均存在起效延迟的问题。本课题组前期工作证实，兼有拮抗5-HT2C受体和抑制5-HT/NE双重重摄取作用的全新结构化合物ZY-1408在多种抑郁动物模型上具有强效抗抑郁效应且比经典5-HT/NE双重重摄取抑制药度洛西汀起效快速；此外，5-HT2C受体激动剂CP-809101能够阻断ZY-1408快速起效的作用，提示5-HT2C受体可能是ZY-1408发挥抗抑郁快速起效作用的关键靶点。本研究以5-HT2C受体为核心，拟通过放射性受体结合、基因过表达、清醒动物脑微透析等手段，在受体、单胺神经递质、神经元生成和神经可塑性等层面，从正反两方面阐明5-HT2C受体在ZY-1408抗抑郁快速起效中的作用及机制，为ZY-1408开发成具有自主知识产权的Ⅰ类新药奠定基础，同时为快速起效的多靶标抗抑郁新药研究提供思路和方法。

目前抗抑郁药物均存在起效延迟的问题。本课题组工作证实，兼有拮抗5-HT2C受体和抑制5-HT/NE双重重摄取作用的全新结构化合物ZY-1408在多种抑郁动物模型上具有强效抗抑郁效应且比经典5-HT/NE双重重摄取抑制药度洛西汀起效快速；此外，5-HT2C受体激动剂CP-809101能够阻断ZY-1408快速起效的作用，证实5-HT2C受体是ZY-1408发挥抗抑郁快速起效作用的关键靶点。本研究以5-HT2C受体为核心，通过放射性受体结合、基因过表达、清醒动物脑微透析等手段，在受体、单胺神经递质、神经元生成和神经可塑性等层面，从正反两方面阐明了5-HT2C受体在ZY-1408抗抑郁快速起效中的作用及机制，为ZY-1408开发成具有自主知识产权的Ⅰ类新药奠定了基础，同时为快速起效的多靶标抗抑郁新药研究提供了思路和方法。