7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders.
7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders.
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DOI：
10.1186/s40035-015-0048-7
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发表时间：
2016
影响因子：
12.6
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
Liu C;Chan CB;Ye K
脑源性神经营养因子(BDNF)主要通过与跨膜受体酪氨酸激酶TrkB结合来调节多种生物学过程。它是许多神经、精神和代谢疾病的潜在治疗靶点。然而，缺乏有效的方法将BDNF输送到体内，这给其临床应用带来了不可逾越的障碍。为了应对这一挑战，我们启动了一项基于细胞的药物筛选，以寻找作为TrkB激动剂的小分子。7，8-二羟基黄酮(7，8-DHF)是我们报道的第一个小分子TrkB激动剂，现已在各种生化和细胞系统中得到广泛验证。通过与TrkB胞外区的结合，7，8-DHF可触发TrkB二聚化，从而诱导下游信号传导。值得注意的是，7，8-DHF具有口服生物活性，可以穿透脑血屏障(BBB)，发挥其在中枢神经系统的神经营养活性。大量报告表明，7，8-DHF在各种动物疾病模型中具有良好的治疗效果，这些疾病与BDNF信号转导不足有关。本文就7，8-DHF的结合活性和特异性，构效关系，药代动力学和代谢，以及临床前对某些人类疾病的疗效等方面的研究进展进行综述。
Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone (7,8-DHF) is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases.