Therapeutic Relevance of Cannabinoids for Alzheimer's Disease

大麻素对阿尔茨海默病的治疗意义

• 批准号: 9977821
• 负责人: Pamela Anne Maher
• 金额: $ 52.91万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977821
• 关键词: Address; Affect; Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Animals; Area; Binding; Bioinformatics; Biological; Biological Assay; Brain; Brain Pathology; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Carbon Dioxide; Cell physiology; Chemicals; Chemistry; Clinic; Cognition; Collaborations; Complex; Data; Dementia; Disease; Drug Screening; Drug Targeting; Endocannabinoids; Flavones; Funding; Gene Expression; Goals; Health; Hemp; Hippocampus (Brain); Human; Investigational Drugs; Laboratories; Lead; Ligands; Medicinal Plants; Medicine; Metabolism; Mississippi; Modeling; Molecular; Molecular Target; Mus; Natural Products; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Phenotype; Plant Extracts; Plants; Plasma; Political Factor; Positioning Attribute; Precipitation; Property; Proteins; Proteomics; Running; Safety; Secure; Structure; Structure-Activity Relationship; System; Technology; Terpenes; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; United States National Institutes of Health; Universities; Work; base; clinical development; drug candidate; drug discovery; endogenous cannabinoid system; familial Alzheimer disease; high reward; high risk; in vivo; interest; mouse model; neuron loss; neuroprotection; new therapeutic target; novel; phase I trial; prevent; receptor; safety testing; screening; small molecule; small molecule libraries; social factors; tau phosphorylation; tissue culture; transcriptome sequencing

Alzheimer's disease (AD) is the most prevalent old age-associated neurodegenerative disease. However, despite extensive interest and financial outlay, drug discovery in this area has not yet yielded any disease modifying compounds. This may be in part due to the small number of molecular targets suitable for drug discovery. Thus, the identification of multiple, new drug targets is still one of the most important challenges. Natural products are the structural basis of the majority of the drugs in the clinic today. Over the last decade we have used a novel phenotypic drug-screening platform based upon toxicities associated with the old brain and natural product chemical libraries and plant extracts to identify compounds that have therapeutic efficacy in multiple models of neurodegeneration and dementia. Structure-activity relationship driven medicinal chemistry was then used to make pharmacologically suitable drug candidates. One of these compounds is in Phase I clinical trials for AD and another has NIH funding for investigational new drug (IND) studies. Perhaps the greatest relatively unexplored area of AD drug discovery is the endocannabinoid system and the compounds in the Cannabis plant that may interact with it and other pathways associated with neurodegeneration. While THC and CBD are the best-studied chemicals in Cannabis, there are over 100 non-psychoactive cannabinoids and 400 other unique chemicals within the plant that may have therapeutic potential. We have recently demonstrated that several of these compounds are exceptionally neuroprotective in our drug screening platform that has already yielded bona fide AD drug candidates. The hypothesis for this high risk, high reward R21 application is that there are non-psychoactive compounds within the Cannabis plant that are suitable lead drug candidates for AD, and that these can be identified, along with their molecular targets, by our drug screening platform and chemical proteomics, respectively. There are three Specific Aims in this application. 1) All commercially available pure cannabinoids, flavones and terpenes in Cannabis, will be screened, a project already underway. In collaboration with Dr. ElSohly at the University of Mississippi, additional pure compounds will be screened that he has isolated as well as complex high CBD Cannabis (hemp) extracts where the most active new compounds will be identified. The pharmacological and safety properties of the five best compounds will be studied. 2) The molecular targets of one will be determined. 3) Finally, the therapeutic efficacy of the best compound will be examined in the 3xFAD transgenic mouse model of familial AD and rapidly aging SAMP8 mice. At the end of two years, a non-psychoactive compound and its target will have been identified and tested in two rigorous models of dementia, gaining a greater understanding of the therapeutic potential of Cannabis as well as identifying a novel lead AD drug candidate and its molecular target.

阿尔茨海默病(AD)是最常见的老年相关神经退行性疾病。然而， 尽管有广泛的兴趣和资金投入，但这一领域的药物发现尚未产生任何疾病 修饰化合物。这在一定程度上可能是由于适用于药物的分子靶标数量较少。 发现号。因此，确定多个新的药物靶点仍然是最重要的挑战之一。 天然产物是当今临床上大多数药物的结构基础。在过去的十年里 我们使用了一种新的表型药物筛选平台，该平台基于与旧脑相关的毒性 和天然产品化学库和植物提取物，以确定具有治疗效果的化合物 在多种神经变性和痴呆症模型中。构效关系驱动型药物 然后，化学被用来制造药理上合适的候选药物。其中一种化合物在 AD的第一阶段临床试验和NIH为研究性新药(IND)研究提供资金的另一阶段。 也许AD药物发现中最大的相对未被探索的领域是内源性大麻系统 大麻植物中可能与之相互作用的化合物以及与之相关的其他途径 神经退行性变。虽然THC和CBD是大麻中研究最深入的化学物质，但有100多种 植物中的非精神活性大麻素和400种其他独特的化学物质可能具有治疗作用 潜力。我们最近证明了其中几种化合物具有特殊的神经保护作用。 在我们的药物筛选平台上，已经产生了真正的AD候选药物。假设 这种高风险、高回报的R21应用是在 大麻植物，适合作为AD的候选铅药物，这些植物可以被识别，以及 与其分子靶点，分别由我们的药物筛选平台和化学蛋白质组学。 这个应用程序有三个具体目标。1)所有市面上可买到的纯大麻类药物， 将对大麻中的黄酮类和萜类进行筛选，这一项目已经在进行中。与Dr. ElSohly在密西西比大学，将筛选出更多的纯化合物，他已经分离出 以及复杂的高CBD大麻(大麻)提取物，其中最活跃的新化合物将是 确认身份。将对这五种最佳化合物的药理和安全性进行研究。2) 其中一个的分子靶标将被确定。3)最后，最佳化合物的治疗效果将是 在家族性AD和快速老化的SAMP8小鼠的3xFAD转基因小鼠模型中进行了检测。在…的末尾 两年内，一种非精神活性化合物及其靶标将在两年内被确定和测试 严格的痴呆症模型，更好地了解 以及确定一种新的AD候选药物及其分子靶点。