Identification and confirmation of blood-brain barrier (BBB) permeability of chemical enhancers of nerve growth factor-dependent neurite outgrowth.

神经生长因子依赖性神经突生长的化学增强剂的血脑屏障（BBB）渗透性的鉴定和确认。

• 批准号: 9211354
• 负责人: Gordon C Ibeanu
• 金额: $ 10.8万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211354
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Architecture; Axon; Basal Nucleus of Meynert; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Cell Death; Cell model; Cell physiology; Cells; Chemical Structure; Chemicals; Chemosensitization; Complex; Computer Simulation; Cues; Data; Defect; Deterioration; Development; Enhancers; Exhibits; Future; Goals; Growth; Hippocampus (Brain); Huntington Disease; Image; In Vitro; Laboratories; Lead; Libraries; Link; Literature; Maintenance; Medical; Methodology; Morphology; Mus; Natural Products; Nerve Growth Factors; Neurites; Neurodegenerative Disorders; Neurons; Neuropeptides; Oxidative Stress; Parkinson Disease; Pathway interactions; Patients; Peptides; Perinatal; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Plants; Population; Positioning Attribute; Probability; Process; Property; Prosencephalon; Proteins; Recombinants; Recovery of Function; Regulation; Reporting; Research; Role; Scheme; Sensory; Series; Signal Pathway; Signal Transduction; Small Molecule Chemical Library; Structure; Synapses; Testing; Therapeutic; Therapeutic Agents; Thiophenes; Toxic effect; Transgenic Organisms; Verbena; Vertebral column; age related; analog; base; cholinergic; direct application; improved; in vivo; lead series; memory acquisition; nerve supply; neuron loss; neurotrophic factor; novel; novel therapeutics; programs; public health relevance; response; restoration; scaffold; screening; small molecule; tool; transmission process

 DESCRIPTION (provided by applicant): Nerve cell death is a gross neuropathologic feature associated with many neurodegenerative diseases. In the case of Alzheimer's disease (AD), deterioration of synaptic connections made by axons and dendritic processes has been linked to the loss of neurotrophic support in the brain centers affected by AD. Several experimental strategies and discovery schemes have been employed as a means to reverse the effects on neuronal architecture but many have not translated into successful therapies. Direct application of nerve growth factor (NGF) has been shown to augment morphological and sometimes functional recovery of degenerating neurons suggesting that a therapeutic approach that enhances the function of neurotrophins could halt or reverse the effects of AD and other neurodegenerative diseases. Our central hypothesis is that small molecules that enhance the activities of neurotrophins are uniquely suited to study the fundamental mechanisms that underlie activity potentiation of neuropeptides by drug-like chemicals in order to identify potentil targets that could lead to development of novel therapeutics for many age-related neurodegenerative diseases. Consequently, we have synthesized and tested Verbenachalcone (VC), a natural product from Verbena litoralis, and several derivatives that promote neurite outgrowth (NOG) in neuronal cell models. In addition, we utilized the dihydrochalcone backbone of VC as a template in a computational model to identify a small molecule B355252 with NGF-dependent NOG promoting activity and neuroprotective properties. Derivatives of the small molecule with improved toxicity profile have been synthesized. However, the SAR studies have not yielded improvements in compound potency. In this project we propose to identify compounds with novel scaffolds different from that of B355252, which synergize with NGF to enhance NOG by implementing a phenotypic image-based screen. In addition, we will develop and validate an in vitro blood- brain permeability assay to test the analogs and hits from the screen for potential to cross the blood-brain barrier and initiate studies on the signaling mechanisms of lead compounds as a prelude for future in vivo compound studies.

 描述（由适用提供）：神经细胞死亡是与许多神经退行性疾病有关的总体神经病理学特征。在阿尔茨海默氏病（AD）的情况下，确定由轴突和树突过程建立的突触连接与受AD影响的大脑中心的神经营养支持的丧失有关。已经采用了几种实验策略和发现方案，以扭转对神经元建筑的影响，但许多人没有转化为成功的疗法。已显示神经生长因子（NGF）的直接应用可以增强形态学，有时甚至是功能恢复神经元的功能恢复，这表明一种增强神经营养蛋白功能的治疗方法可以停止或逆转AD和其他神经退行性疾病的影响。我们的中心假设是，增强神经营养蛋白活性的小分子非常适合研究通过类似药物的化学物质对神经肽增强活性增强活性增强的基本机制，以识别可能导致许多年龄相关神经性疾病的新型治疗的潜在靶标。因此，我们已经合成和测试了词曲纳龙（VC），Verbena litoralis的天然产物以及几种在神经元细胞模型中促进神经蛋白神经产物（NOG）的衍生物。此外，我们利用VC的二氢chalcone主链作为计算模型中的模板来识别具有NGF依赖性NOG促进活性和神经保护特性的小分子B355252。已经合成了具有改善毒性特征的小分子的衍生物。但是，SAR研究尚未提高复合效力。在这个项目中，我们建议鉴定具有与B355252不同的新型脚手架的化合物，该化合物与NGF协同作用，以通过实现基于表型图像的屏幕来增强NOG。此外，我们将开发和验证体外血脑内的通透性评估，以测试屏幕上的类似物和命中，以便跨越血脑屏障，并开始研究铅化合物的信号传导机制，以此作为未来体内化合物研究的前奏。