Systematic Investigation of Rare Cannabinoids with Pain Receptors

项目总结 几个世纪以来，从大麻植物中提取的药物一直被用来治疗疼痛。近期 对大麻及相应的大麻素类药物治疗疼痛的临床效果的认识 一直专注于两种主要的植物大麻素，三角洲-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昏昏欲睡。另一方面，还有更多 110已知的少量植物大麻素；然而，只有少数有限的研究与其止痛特性有关 存在到目前为止。研究稀有大麻素的主要障碍是它们的可获得性有限。数不胜数 植物提取物混合物的提纯通常只提供毫克量的纯化合物 1000公斤的植物材料，使得这种努力非常不切实际，也不可持续。事实上，大多数 NIDA的药物供应计划(DSP)中没有商业用途或列出的少量植物大麻素。AS 合成有机化学家和生物学家，独特地位于化学和生物学的交界处，我们的 研究方案致力于以可持续和可持续的方式为供应问题提供解决方案 实践合成以及进行基础生物学研究。通过提供访问稀有 通过合成手段，我们希望消除供应障碍，作为研究的先决条件 它们的止痛特性。具体地说，该提案描述了几类稀有的合成方法 植物大麻素及其在小胶质细胞中的抗炎潜力的系统评价。小调 具有较强抗炎作用的大麻类化合物将对其激动性/拮抗性进行进一步的评估 主要的内源性痛觉回路系统包括大麻素受体(CB1、CB2、GPR55)和 香草样/瞬时受体电位阳离子通道V亚家族(TRPV)、A亚家族(TRPA)、M亚家族 (TRPM)。预计这些研究将建立明确的稀有药物的药理特性。 植物大麻素与参与痛觉的主要受体有关。

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.