Multipotent Neurotrophin Antagonist Targets Brain-Derived Neurotrophic Factor and Nerve Growth Factor
Multipotent Neurotrophin Antagonist Targets Brain-Derived Neurotrophic Factor and Nerve Growth Factor
复制标题
DOI：
10.1124/jpet.109.159079
复制
发表时间：
2010-02-01
影响因子：
3.5
通讯作者：
Ross, G. M.
中科院分区：
文献类型：
--
作者：
Eibl, J. K.;Chapelsky, S. A.;Ross, G. M.
脑源性神经营养因子（BDNF）和神经生长因子（NGF）是神经营养因子家族的成员，通常在神经系统的发育和维持中发挥作用。然而，神经营养因子失调已经涉及几种神经退行性疾病和精神障碍，包括阿尔茨海默病、帕金森病、神经性疼痛、抑郁症和物质滥用。尽管神经营养因子在神经系统中发挥着重要作用，但已被证明是一个难以捉摸的药理学靶点。在这里，我们描述了一种新的多能神经营养素拮抗剂，3-[（5E）-4-氧代-5-[[5-（4-氨磺酰基苯基）-2-呋喃基]亚甲基]-2-硫代噻唑烷-3-基]丙酸（Y1036）。Y1036结合BDNF（K-D = 3.5 +/- 0.3 μ M）和NGF（K-D = 3.0 +/- 0.4 μ M），阻止BDNF或NGF与它们的专性受体相互作用。Y1036阻止BDNF和NGF介导的trk激活、p44/42丝裂原活化蛋白激酶途径的下游激活和神经营养因子介导的背根神经节感觉神经元的分化。BDNF和NGF特异性拮抗剂的鉴定在研究和治疗涉及多种神经营养因子失调的疾病中具有相当大的意义。
Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are members of the neurotrophin family that normally play a role in the development and maintenance of the nervous system. However, neurotrophin dysregulation has been implicated in several neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, Parkinson's disease, neuropathic pain, depression, and substance abuse. Despite their central role in the nervous system, neurotrophins have proved to be an elusive pharmacological target. Here, we describe a novel multipotent neurotrophin antagonist, 3-[(5E)-4-oxo-5-[[5-(4-sulfamoylphenyl)-2-furyl]methylene]-2-thioxo-thiazolidin-3-yl]propanoic acid (Y1036). Y1036 binds BDNF (K-D = 3.5 +/- 0.3 mu M) and NGF (K-D = 3.0 +/- 0.4 mu M) preventing either BDNF or NGF from interacting with their obligate receptor(s). Y1036 prevents both BDNF- and NGF-mediated trk activation, downstream activation of the p44/42 mitogen-activated protein kinase pathway, and neurotrophin-mediated differentiation of dorsal-root ganglion sensory neurons. Identification of a BDNF- and NGF-specific antagonist is of considerable interest in the study and treatment of diseases where dysregulation of multiple neurotrophins has been implicated.