PDF(Pubmed)
Abstract：
One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders.
摘要：
在神经退行性疾病中最有害的一个常见事件，尽管它们有复杂的发病机制，是神经元死亡率的增加。内源性神经营养蛋白由主要的神经保护因子组成，而脑源性神经营养因子（BDNF）及其高亲和力酪氨酸激酶受体TrkB因其重要的神经元作用而在许多研究中被描述。这种受体的正常功能对神经元存活至关重要，分化,和突触功能。然而,研究表明，除了直接激活，TrkB受体可以通过GPCR被反式激活。已经证明，5-HT4受体的激活和TrkB受体的反式激活对神经元分化具有积极影响（总树突长度，初级树突的数量，和分支指数)。因此，基于已知的TrkB受体激活剂LM22A-4的主要结构特征，和部分5-HT4受体激动剂RS67333，我们设计并合成了一组具有潜在双重活性的新型化合物的小数据集，以便不仅防止神经元死亡，而且在神经退行性疾病中诱导神经元分化。
