Synthesis of cannabidiol dimers as potential agents to treat neurological disorders

新冠疫情加剧了美国民众的压力、焦虑和抑郁。现行FDA 批准的治疗这些疾病的药物只在亚群中有效， 患者必须尝试多种方案才能找到一种有效的方案。毫不奇怪，患者继续 寻求自我治疗的替代补救办法，例如，大麻然而，尽管合法化 大麻在许多州及其广泛用于这些目的，大麻是一种多样化的混合物， 数百种化合物，其含量因大麻来源而异。一种活性 大麻的主要成分大麻二酚（CBD）已经被单独研究其药用活性。 Epidiolex®是一种高度纯化的CBD，被FDA批准用于治疗罕见的癫痫。问题是 CBD -以其天然形式-是一种非特异性（多药理学）剂。CBD弱激活几个 以下类别的受体：大麻素、阿片样物质、5-羟色胺（5-HT 1A，5-HT 2A）、β-GPR 55， 腺苷和TRP受体等。目前尚不清楚是哪种受体和信号通路 对CBD的积极效益至关重要。我们的长期目标是确定和扩展新的治疗方法 具有针对神经/精神障碍的明确的特定作用机制。因此，总体而言， 本申请的目的是产生新的CBD二聚体，所述CBD二聚体被提出对大麻素是特异性的 或血清素受体。我们将评估CBD同源/异源二聚体将增强 通过在二聚体受体上的二价或双位结合与大麻素和5-羟色胺受体选择性结合 或分别在两个位点上的单个受体。在产生我们的CBD同/异二聚体后， 文库中，我们将评估它们对上述受体的选择性，我们还将评估 精神活性受体面板（NIMH-PDSP）。这将使我们能够建立关键的初步数据， NIH申请。开发这些新的二聚体作为化学生物学探针将阐明相互作用 CBD与5-羟色胺和大麻素受体以及这些活动背后的结构细节。最后， 这些CBD半合成衍生物具有产生有利的治疗指数的潜力 压力、焦虑和抑郁。结果与我们的假设一致，将有广泛的公共卫生 影响，因为社会对生物多样性公约的兴趣，尽管它的活动知之甚少， 迫切需要安全有效的治疗方法。重要的是，如果成功，长期目标是向有希望的方向发展。 化合物进入先进的临床前测试。

The COVID pandemic has worsened stress, anxiety, and depression in the US population. Current FDA approved therapeutics for these ailments are only effective in subpopulations, and it is very common for patients to have to attempt multiple regimens to find one that works. Not surprisingly, patients continue seeking alternative remedies for self-treatment, e.g., cannabis. However, regardless of the legalization of cannabis in many states and its widespread usage for these purposes, cannabis is a diverse mixture of hundreds of compounds that widely vary in amount depending on the cannabis source. One active component of cannabis, cannabidiol (CBD), has been individually studied for its medicinal activity. Epidiolex®, a highly purified form of CBD, is FDA approved to treat rare forms of epilepsy. The issue is that CBD – in its natural form – is a non-specific (poly-pharmacological) agent. CBD weakly activates several receptors of the following classes: cannabinoid, opioid, serotonin (5-HT1A, 5-HT2A), orphan-GPR55, adenosine, and TRP receptors, among others. It remains unclear which receptor(s) and signaling pathway(s) are crucial for the positive benefits of CBD. Our long-term goal is to identify and expand novel therapeutics with defined, specific mechanisms of action for neurological/mental disorders. In this light, the overall objective in this application is to create novel CBD dimers that are proposed to be specific to cannabinoid or serotonin receptors. We will assess the hypothesis that CBD homo/heterodimers will enhance the selective binding to cannabinoid and serotonin receptors through bivalent or bitopic binding on dimerreceptors or a single receptor on two sites, respectively. Upon generation of our CBD homo/heterodimer library, we will evaluate their selectivity for the above receptors, and we will also evaluate dimers in a psychoactive receptor panel (NIMH-PDSP). This will position us to build key preliminary data for a competitive NIH application. Development of these novel dimers as chemical biology probes will elucidate the interactions of CBD with serotonin and cannabinoid receptors and the structural details behind these activities. Ultimately, these CBD semisynthetic derivatives have the potential to yield favorable therapeutic indices for the treatment of stress, anxiety, and depression. Results consistent with our hypothesis will have wide-ranging public health implications because of societal interest in CBD despite its poorly understood activities and because of the urgent need for safe, effective therapies. Importantly, if successful, the long-term goal is to move promising compounds into advanced preclinical testing.