Small Molecule Trk Receptor Agonists and Other Neurotrophic Factor Mimetics
Small Molecule Trk Receptor Agonists and Other Neurotrophic Factor Mimetics
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DOI：
10.2174/1568007023339490
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发表时间：
2002-01-01
影响因子：
3
通讯作者：
Harper, Sarah J.
中科院分区：
文献类型：
--
作者：
Pollack, Scott J.;Harper, Sarah J.
神经生长因子属于蛋白质的小家族，其在Trk和p75（NTR）跨膜受体处的结合触发信号传导事件的级联，所述信号传导事件在神经元细胞中和在体内引起神经营养反应。在神经退行性疾病的动物模型中，神经营养因子具有强大的作用，已被评估用于治疗几种人类神经退行性疾病。然而，主要由于这些蛋白质的不良药代动力学行为，它们在临床上很大程度上没有成功，使得需要开发小分子神经营养因子模拟物。描述了一系列化合物，其通过多种机制实现归因于神经营养因子的一些神经营养和神经保护作用。这些小分子分为以下功能类别：（1）直接激活Trk受体的化合物;（2）增强神经营养因子对Trk受体的作用的化合物;（3）间接激活Trk的化合物;（4）影响神经营养因子表达或分泌的化合物;和（5）在Trk受体下游或独立于Trk受体起作用的广泛类别的化合物。不幸的是，已经报道的大多数化合物或者缺乏对所需机制/作用的特异性，或者缺乏化合物在适当的体内模型中的功效，或者两者兼而有之。这第二个限制对于设计用于模拟神经营养因子与Trk受体相互作用的化合物特别严重，这是一个持续的和艰巨的挑战。然而，一小部分化合物作用于Trk受体下游的细胞内信号传导途径，显示出未来治疗神经退行性疾病的前景。
Nerve growth factor belongs to a small family of proteins whose binding at the Trk and p75(NTR) transmembrane receptors triggers a cascade of signaling events that give rise to neurotrophic responses in neuronal cells and in vivo. Following their robust effects in animal models of neurodegeneration, neurotrophins have been evaluated for therapy for several human neurodegenerative diseases. However, due mainly to the poor pharmacokinetic behavior of these proteins, they have largely met without success in the clinic, making it desirable to develop small molecule neurotrophin mimetics. A range of compounds is described that achieves some of the neurotrophic and neuroprotective effects attributed to neurotrophins through a variety of mechanisms. These small molecules are divided into the following functional categories: (1) compounds that activate Trk receptors directly; (2) compounds that potentiate the actions of neurotrophins on Trk receptors; (3) compounds that activate Trk indirectly; (4) compounds that influence neurotrophin expression or secretion; and (5) a broad class of compounds that act downstream of, or independently of, Trk receptors. Unfortunately, most of the compounds that have been reported suffer from either lack of specificity for the desired mechanism/effect(s) or lack of efficacy of the compounds in appropriate in vivo models, or both. This second limitation has been particularly severe for compounds designed to mimic the neurotrophins in their interaction with Trk receptors, an ongoing and formidable challenge. Nevertheless, a small subset of the compounds, acting on intracellular signaling pathways downstream of Trk receptors, shows promise for the future treatment of neurodegenerative diseases.