Therapeutic Relevance of Cannabinoids for Alzheimer's Disease

阿尔茨海默病（Alzheimer's disease，AD）是最常见的老年性神经退行性疾病。但是，在这方面， 尽管有广泛的兴趣和资金投入，在这一领域的药物发现还没有产生任何疾病 改性化合物。这可能部分是由于适用于药物治疗的分子靶点数量很少。 的发现因此，确定多个新的药物靶标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。在过去十年中 我们使用了一种新的基于与老年大脑相关的毒性的表型药物筛选平台， 以及天然产物化学文库和植物提取物来鉴定具有治疗功效的化合物 神经退化和痴呆的多种模型中。构效关系驱动的药物 然后使用化学方法来制备合适的候选药物。其中一种化合物 AD的I期临床试验和另一项NIH资助的新药研究（IND）。 也许AD药物发现中最大的相对未开发的领域是内源性大麻素系统 以及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。 神经变性虽然THC和CBD是大麻中研究最多的化学物质，但有超过100种 非精神活性大麻素和400种其他独特的化学物质， 潜力我们最近已经证明，这些化合物中有几种是非常神经保护的 我们的药物筛选平台已经产生了真正的AD候选药物。假设为 这种高风险，高回报的R21应用是，有非精神活性化合物内， 大麻植物是AD的合适的主要候选药物，并且这些可以被识别，沿着 与它们的分子靶点，分别通过我们的药物筛选平台和化学蛋白质组学。 该应用程序有三个具体目标。1)所有市售的纯大麻素， 将对大麻中的黄酮和萜烯进行筛选，这一项目已经在进行中。与博士合作。 密西西比大学的ElSohly博士说，将筛选他分离出的其他纯化合物， 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 鉴定将研究五种最佳化合物的药理学和安全性。2)的 将确定其中一个的分子目标。3)最后，最佳化合物的治疗效果将是 在家族性AD的3xFAD转基因小鼠模型和快速老化的SAMP8小鼠中检查。结束时 在两年的时间里，一种非精神活性化合物及其靶点将在两年内被确定和测试。 严格的痴呆模型，更好地了解 大麻以及确定一种新的领先的AD候选药物及其分子靶点。

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.