Systematic Investigation of Rare Cannabinoids with Pain Receptors

具有疼痛感受器的稀有大麻素的系统研究

• 批准号: 10018722
• 负责人: Aditi Das
• 金额: $ 18.23万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018722
• 关键词: ARNT gene; Agonist; Analgesics; Anti-Inflammatory Agents; Area; Biological; Biological Assay; Biology; CNR1 gene; CNR2 gene; Calcium; Cannabidiol; Cannabinoids; Cannabis; Cations; Cells; Chemistry; Collaborations; Development; Drowsiness; Evaluation; Flavonoids; Future; GPR55 receptor; Goals; Human; Investigation; Kilogram; Knowledge; Letters; Libraries; Measurement; Measures; Methods; Microglia; Minor; Mission; National Institute of Drug Abuse; Outcome; Pain; Pain Research; Pain management; Pharmaceutical Preparations; Pharmacology; Phytochemical; Plant Extracts; Plant Sources; Plants; Property; Public Health; Receptor Activation; Reporting; Research; Sedation procedure; Structure; System; TRP channel; Terpenes; Testing; Tetrahydrocannabinol; Therapeutic; United States National Institutes of Health; Vanilloid; Work; base; beta-arrestin; cannabinoid receptor; chemical synthesis; clinical effect; innovation; milligram; neuroinflammation; next generation; novel; pain receptor; pain sensation; phytocannabinoid; programs; receptor; receptor expression; recruit; synthetic cannabinoid

PROJECT SUMMARY Remedies derived from the cannabis plants have been used for management of pain for centuries. Recent understanding of the clinical effects of cannabis and the corresponding cannabinoids in the treatment of pain has been focused on two major phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Though effective, these compounds cause sedation and drowsiness. On the other hand, there are more than 110 known minor phytocannabinoids; however, only a few limited studies related to their analgesic properties exists to date. The major obstacle in studying rare cannabinoids is their limited availability. Numerous purifications of plant extracts mixtures usually provide only milligram quantities of pure compounds from kilograms of plant material, making such endeavors highly nonpractical as well as unsustainable. In fact, most of minor phytocannabinoids are not commercially available or listed in NIDA’s Drug Supply Program (DSP). As synthetic organic chemists and biologists, uniquely situated at the interface of chemistry and biology, our research programs are devoted to providing solutions to the supply problem in the form of sustainable and practical syntheses as well as performing fundamental biological studies. By providing an access to rare phytochemicals by synthetic means, we expect to remove the barrier of supply as a prerequisite for studying their analgesic properties. Specifically, this proposal describes synthetic approaches to several classes of rare phytocannabinoids and systematic evaluation of their anti-inflammatory potential in microglial cells. Minor cannabinoids with strong anti-inflammatory will undergo further evaluation towards their agonism/antagonism of major endogenous pain circuitry systems including cannabinoid receptors (CB1, CB2, GPR55) and vanilloid/transient receptor potential cation channel subfamily V (TRPV), subfamily A (TRPA), subfamily M (TRPM). It is expected that these studies will establish well-defined pharmacological properties of rare phytocannabinoids with respect to the major receptors involved in pain sensation.

项目摘要 几个世纪以来，从大麻植物中提取的药物一直被用于治疗疼痛。最近 了解大麻和相应的大麻素在治疗疼痛中的临床效果 研究重点是两种主要的植物大麻素，δ-9-四氢大麻酚（THC）和大麻二酚（CBD）。 虽然有效，但这些化合物会引起镇静和嗜睡。另一方面， 110种已知的次要植物大麻素;然而，只有少数有限的研究与其镇痛特性有关 存在至今。研究稀有大麻素的主要障碍是其有限的可用性。许多 植物提取物混合物的纯化通常仅提供毫克量的纯化合物 公斤的植物材料，使这样的努力非常不切实际，以及不可持续的。其实大部分 少量的植物大麻素没有市售或列入NIDA的药物供应计划（DSP）。作为 合成有机化学家和生物学家，独特地位于化学和生物学的界面，我们的 研究计划致力于以可持续和可持续的方式解决供应问题， 实际合成以及进行基础生物学研究。通过提供一个获取稀有 植物化学物质的合成手段，我们希望消除供应的障碍，作为研究的先决条件 它们的止痛特性具体而言，该提案描述了几类稀有化合物的合成方法。 植物大麻素及其在小胶质细胞中抗炎潜力的系统评价。轻微 具有强抗炎作用的大麻素将对其激动/拮抗 主要的内源性疼痛回路系统，包括大麻素受体（CB 1，CB 2，GPR 55）和 香草酸/瞬时受体电位阳离子通道亚家族V（TRPV）、亚家族A（TRPA）、亚家族M （TRPM）。预计这些研究将建立罕见的明确的药理学特性， 植物大麻素相对于涉及痛觉的主要受体的作用。