苔黑酚葡萄糖苷类似物的设计、合成及抗抑郁活性筛选

发布时间：2018-01-20 12:23

本文关键词： 抑郁症神经可塑性小分子糖苷抗抑郁活性筛选　出处：《云南大学》2015年硕士论文　论文类型：学位论文

【摘要】：抑郁症是一种发病率高、危害严重的精神疾病。其发病机制复杂,目前学界提出的机制包括单胺假说、HPA轴假说、神经营养假说、炎症因子假说、表观遗传假说和神经可塑性假说等。现有抗抑郁药物主要包括选择性5-羟色胺再摄取抑制剂(Selective serotonin reuptake inhibitors, SSRI)、选择性5-羟色胺以及去甲肾上腺素再摄取抑制剂(Serotonin and norepinephrine reuptake inhibitors, SNRI)等。约30%的患者对现有药物治疗无响应。而且,常用的抗抑郁药物大多具有起效慢的缺陷,也存在很多副作用。开发新靶点新机理的抗抑郁药已经成为临床迫切需要。传统中药仙茅中分离提取的苔黑酚葡萄糖苷具有改变突触可塑性,增强实验动物学习与记忆的药理活性,是一类机制新颖的抗抑郁活性化合物。本论文以苔黑酚葡萄糖苷为先导化合物,通过更换苷元部分和糖基部分,以及变化苷键构型,对其进行进一步分子结构优化,共合成了21个化合物。所有化合物结构均得到1H-NMR、13C-NMR和HRMS等数据的证实。本研究采取小鼠悬尾实验(TST)和小鼠强迫游泳实验(FST)动物模型,利用原型化合物苔黑酚葡萄糖苷(OR-1)作参照,对合成的3个化合物OR-A、OR-G、 OR-X进行抗抑郁活性筛选。结果显示：化合物OR-1、OR-A、OR-G、OR-X在灌胃20mg/kg剂量下没有产生抗抑郁活性。化合物OR-A (20mg/kg, i.g.)延长悬尾实验的不动时间,对强迫游泳实验的不动时间无影响；而化合物OR-G和OR-X (20mg/kg, i.g.)显著延长了小鼠悬尾实验和强迫游泳实验的不动时间(P0.01),提示这两个化合物可能具有镇静作用。
[Abstract]:Depression is a high incidence of serious mental disease. Its pathogenesis is complex, the academic circles put forward the mechanism including the monoamine hypothesis, HPA axis hypothesis, neurotrophic hypothesis hypothesis, inflammatory factors, epigenetic hypothesis and neural plasticity hypothesis. Existing antidepressant drugs mainly include selective serotonin re 5- (Selective serotonin reuptake inhibitors uptake inhibitor, SSRI 5-), selective serotonin and norepinephrine reuptake inhibitor (Serotonin and norepinephrine reuptake inhibitors, SNRI). About 30% of the patients with no response to existing drugs. Moreover, antidepressants have slow onset of defects, there are many side effects. The mechanism of the development of a new target of antidepressants has become urgent clinical needs. The extraction and separation of traditional Chinese medicine Xianmao in orcinol glucoside has the change of synaptic plasticity Sex, enhancing the pharmacological activity of learning and memory of experimental animals, is a kind of novel antidepressant compound.
The orcinol glucoside as the lead compound, by replacing the aglycone and sugar moieties, and the change of glycoside bond configuration, further optimize the molecular structure on the 21 compounds were synthesized. The structures of all compounds were 1H-NMR, 13C-NMR and HRMS data confirmed.
This research adopts the mouse tail suspension test (TST) and mice forced swimming test (FST) animal model, using the prototype compound orcinol glucoside (OR-1) as a reference, OR-G of the 3 compounds OR-A, OR-X synthesis, screening of antidepressant activity. The results showed that compounds OR-1, OR-A, OR-G, OR-X have antidepressant activity in gastric lavage at a dose of 20mg/kg. Compound OR-A (20mg/kg, i.g.) prolonged immobility time in tail suspension test, the immobility time of the forced swimming test has no effect; and compounds OR-G and OR-X (20mg/kg, i.g.) significantly prolonged immobility time in tail suspension test and the forced swimming test (P0.01), suggesting that these two compounds may have a calming effect.

【学位授予单位】：云南大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R914;R965

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