Small molecules activating TrkB receptor for treating a variety of CNS disorders.
Small molecules activating TrkB receptor for treating a variety of CNS disorders.
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DOI：
10.2174/18715273113129990089
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
Yan Zeng;Xiaonan Wang;Qiang Wang;Shumin Liu;Xiamin Hu;S. McClintock
中科院分区：
文献类型：
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作者：
Yan Zeng;Xiaonan Wang;Qiang Wang;Shumin Liu;Xiamin Hu;S. McClintock
脑源性神经营养因子（BDNF）及其高亲和力受体原肌球蛋白受体激酶B（Trk B）在神经元的分化和存活、突触可塑性和记忆中起着关键作用。事实上，两者都与许多疾病的病理生理学有关。尽管BDNF的显著治疗潜力在过去十年中产生了许多研究，但不良的药代动力学和不良副作用特征限制了BDNF的临床用途。模拟BDNF的神经营养信号并克服药代动力学和副作用障碍的小化合物可能具有更大的治疗潜力。本文综述了BDNF小分子模拟物和选择性TrkB激动剂的研究进展。特别关注TrkB激动剂7，8-二羟基黄酮，其调节多种功能，并在多种中枢神经系统疾病模型中显示出显著的治疗功效。本综述中包括的另外两种小分子是腺苷A2 A受体激动剂，其间接激活TrkB，和BDNF的TrkB结合结构域，环II-LM 22 A化合物，其直接激活TrkB。这些替代分子已在临床前研究中显示出前景，并可能包括在前瞻性临床研究中。
The brain-derived neurotrophic factor (BDNF) and its high affinity receptor tropomyosin-receptor-kinase B (TrkB) play a critical role in neuronal differentiation and survival, synapse plasticity, and memory. Indeed, both have been implicated in the pathophysiology of numerous diseases. Although the remarkable therapeutic potential of BDNF has generated much research over the past decade, the poor pharmacokinetics and adverse side effect profile have limited its clinical usefulness of BDNF. Small compounds that mimic BDNF's neurotrophic signaling and overcome the pharmacokinetic and side effect barriers may have greater therapeutic potential. The purpose of this review is to provide a survey of the various strategies taken towards the development of small molecule mimetics for BDNF and the selective TrkB agonist. A particular focus was placed on TrkB agonist 7, 8-dihydroxyflavone, which modulates multiple functions and has demonstrated remarkable therapeutic efficacy in a variety of central nervous system disease models. Two other small molecules included in this review are adenosine A2A receptor agonists that indirectly activate TrkB, and TrkB binding domains of BDNF, loop II-LM22A compounds that directly activate TrkB. These alternative molecules have shown promise in preclinical studies and may be included in prospective clinical investigations.