喹啉并四唑类抗抑郁先导化合物的发现及结构优化

Clinical depression severely affects a person's family and personal relationships, work or school life, leading to a great harm for society. The current available antidepressants were limited by the onset delay or toxicity profiles. Therefore, searching for new antidepressants which can break through the limits is very important. In our previous work, some tetrazolo[1,5-a]quinoline derivatives were found to significantly reduce the immobility time of forced swimming mice and increase the level of serotonin (5-HT) and norepinephrine (NE) in the brain of mice. Addition, these compounds also significantly increased the number of head-twitches induced by 5-hydroxytryptophan (5-HTP) and the lethality induced by yohimbine. This finding suggested that the mechanisms of enhancing 5-HT and NE function might potentially be involved in their antidepressant-like profile.Based on the above point, over 200 tetrazole derivatives were designed using the tetrazolo[1,5-a]quinoline as the lead compound in this study. The antidepressant activity of these compounds will be evaluated by the forced swimming test. The structure-activity relationships (SARs) will be given. Following the preliminary screening phase, about 20 compounds with better antidepressant activity will be obtained which would be subjected to the further trials for mechanism research. These trials include 5-HTP-induced mouse head-twitch test, yohimbine toxicity potentiation test, reserpine reversal test, the assay of monoamine neurotransmitters in brain of mice, the rat cerebral synaptosome [3H]-5-HT and [3H]-NE reuptake inhibition test. Finally, one or two candidate compounds will be selected for the preclinical study, which could lay the foundation for the development of new antidepressant agents with intellectual property.

抑郁症严重影响了患者的生活和工作，现有抗抑郁药起效慢，毒副作用大，研究开发新抗抑郁药具有重要意义。前期实验结果喹啉并四唑类衍生物在小鼠强迫游泳实验中明显缩短不动时间，增加小鼠脑组织5-羟色胺和去甲肾上腺素含量，并显著性地增加5-羟基色氨酸诱导的小鼠甩头次数，增强育亨宾引起的死亡。其作用机制可能是通过增强5-HT和NE功能而发挥抗抑郁作用。本课题以新颖的喹啉并四唑为先导化合物，按照新药设计原理，设计和合成四唑类新目标化合物共200个左右。以小鼠强迫游泳实验方法，评价抗抑郁作用，阐明构效关系，从中筛选出抗抑郁作用较强的20个左右，对其进行5-羟色胺酸诱导甩头实验、育亨宾毒性增强实验、利血平拮抗实验、小鼠脑组织单胺神经递质的含量测定，大鼠突出体[3H]-5-HT和[3H]-NE 重摄取抑制实验，阐明可能的作用机制。从中发现候选药物1-2个，为开发出具有知识产权的抗抑郁药奠定基础。

抑郁症严重影响了患者的生活和工作，现有抗抑郁药起效慢，毒副作用大，研究开发新抗抑郁药具有重要意义。前期实验结果喹啉并四唑类衍生物在小鼠强迫游泳实验中明显缩短不动时间，增加小鼠脑组织5-羟色胺和去甲肾上腺素含量，并显著性地增加5-羟基色氨酸诱导的小鼠甩头次数，增强育亨宾引起的死亡。其作用机制可能是通过增强5-HT和NE 功能而发挥抗抑郁作用。本课题以新颖的喹啉并四唑为先导化合物，按照新药设计原理，设计和合成了四唑类新目标化合物共200 个左右。这些包括4-（取代苯基）四唑并[1,5-a]喹唑啉类衍生物、嘌呤[2,3-d]并嘧啶类衍生物、吡啶并[2，3-d]嘧啶类衍生物、5-烷基-6，7，8，9，-四氢-苯并噻嗪[3,2-e]四唑并[1,5-a]嘧啶类衍生物。以小鼠强迫游泳实验方法，评价抗抑郁作用。本课题阐明了四唑并[1,5-a]类衍生物的结构与活性之间的关系，为开发新的抗抑郁药奠定了基础。