Synthesis of cannabidiol dimers as potential agents to treat neurological disorders

新冠肺炎的流行加剧了美国人的压力、焦虑和抑郁。美国食品和药物管理局 经批准的治疗这些疾病的方法只在亚群中有效，并且对于 患者必须尝试多种方案才能找到有效的方案。不足为奇的是，患者继续 寻求自我治疗的替代疗法，例如大麻。然而，无论是否合法化， 大麻在许多州及其广泛使用用于这些目的，大麻是一种多样化的混合物 根据大麻来源的不同，数量有很大差异的数百种化合物。一个处于活动状态 大麻的成分大麻二酚(CBD)因其药用活性而被单独研究。 Epidiolex®是一种高纯度的CBD，已获FDA批准用于治疗罕见形式的癫痫。问题是， CBD--以其自然形式--是一种非特异性(多元药理)制剂。CBD弱激活了几个 受体如下：大麻素，阿片，5-羟色胺(5-HT1A，5-HT2A)，孤儿-GPR55， 腺苷和色氨酸受体等。目前还不清楚是哪种受体(S)和信号通路(S) 对于CBD的积极效益至关重要。我们的长期目标是发现和推广新的治疗方法 对神经/精神障碍有明确、具体的作用机制。从这个角度来看，总体上 本应用的目的是创造新的CBD二聚体，这些二聚体被认为是针对大麻素的 或5-羟色胺受体。我们将评估CBD同/异二聚体将增强 通过二聚体受体上的二价或双位结合选择性结合大麻素和5-羟色胺受体 或分别在两个位置上的单个受体。在我们的CBD同/异二聚体产生时 文库中，我们将评估它们对上述受体的选择性，我们还将评估一种 精神活性受体面板(NIMH-PDSP)。这将使我们能够为具有竞争力的 美国国立卫生研究院申请。这些新型二聚体作为化学生物探针的开发将有助于阐明相互作用 关于CBD与5-羟色胺和大麻素受体的关系以及这些活动背后的结构细节。最终， 这些CBD半合成衍生物有可能为治疗提供有利的治疗指标。 压力、焦虑和抑郁。与我们的假设一致的结果将对公共卫生产生广泛的影响 影响，因为社会对CBD的兴趣，尽管它的活动鲜为人知，因为 迫切需要安全有效的治疗方法。重要的是，如果成功，长期目标是取得有希望的进展。 将化合物转化为高级临床前试验。

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.