Synthesis of cannabidiol dimers as potential agents to treat neurological disorders

大麻二酚二聚体的合成作为治疗神经系统疾病的潜在药物

• 批准号: 10737873
• 负责人: Francisco Leon
• 金额: $ 20.42万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737873
• 关键词: Adenosine; Anxiety; Binding; Biology; COVID-19 pandemic; Cannabidiol; Cannabinoids; Cannabis; Chemicals; Data; Development; Epidiolex; Epilepsy; FDA approved; GPR55 receptor; Generations; Goals; HTR2A gene; Homo; Individual; Libraries; Light; Medicine; Mental Depression; Mental disorders; National Institute of Mental Health; Neurologic; Opioid; Orphan; Patients; Population; Positioning Attribute; Preclinical Testing; Public Health; Regimen; Serotonin; Signal Pathway; Site; Source; Stress; Therapeutic; Therapeutic Index; United States National Institutes of Health; Work; cannabinoid receptor; dimer; effective therapy; interest; marijuana legalization; nervous system disorder; novel; novel therapeutics; receptor; serotonin receptor; targeted treatment

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.

新冠疫情大流行加剧了美国民众的压力、焦虑和抑郁。目前FDA 针对这些疾病的批准疗法仅对亚人群有效，并且这种情况很常见 患者必须尝试多种治疗方案才能找到有效的治疗方案。毫不奇怪，患者继续 寻求自我治疗的替代疗法，例如大麻。然而，无论合法化 大麻在许多州及其广泛用于这些目的，大麻是多种混合物 数百种化合物的含量因大麻来源而异。一位活跃 大麻的成分大麻二酚（CBD）的药用活性已被单独研究。 Epidiolex® 是 CBD 的高度纯化形式，已获得 FDA 批准用于治疗罕见形式的癫痫症。问题是 天然形式的 CBD 是一种非特异性（多药理）制剂。 CBD 弱激活多种 以下类别的受体：大麻素、阿片类药物、血清素（5-HT1A、5-HT2A）、孤儿-GPR55、 腺苷和 TRP 受体等。目前尚不清楚哪些受体和信号通路 对于 CBD 的积极效益至关重要。我们的长期目标是识别和扩展新疗法 对于神经/精神疾病有明确的、具体的作用机制。如此看来，总体 本申请的目标是创建新型 CBD 二聚体，该二聚体被提议专门针对大麻素 或血清素受体。我们将评估 CBD 同源/异源二聚体将增强 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血清素受体 或分别在两个位点上的单个受体。在我们的 CBD 同源/异源二聚体生成后 文库中，我们将评估它们对上述受体的选择性，我们还将评估二聚体 精神活性受体组（NIMH-PDSP）。这将使我们能够为具有竞争力的产品建立关键的初步数据 美国国立卫生研究院的申请。开发这些新型二聚体作为化学生物学探针将阐明相互作用 CBD 与血清素和大麻素受体的结合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产生有利的治疗指数 压力、焦虑和抑郁。与我们的假设一致的结果将产生广泛的公共卫生影响 尽管人们对 CBD 的活动知之甚少，但由于社会对 CBD 的兴趣，以及由于 迫切需要安全、有效的治疗方法。重要的是，如果成功，长期目标是推动有前途的 化合物进入高级临床前测试。