CNS Drug Discovery from the Ocean: Cyanobacterial Secondary Metabolites to Treat Comorbid Pain and Depression

项目总结/摘要 该提案将使用新型海洋天然产品用于研究和治疗疼痛，抑郁，焦虑， 以及疼痛和情感障碍的共病情况。最近的证据表明， 慢性疼痛和抑郁/焦虑之间的相互作用。特别地，慢性疼痛（例如纤维肌痛、慢性疼痛）可以是疼痛性的。 下背痛，膀胱疼痛综合征）似乎在流行病学和生物学上都与 抑郁/焦虑。在这种情况下，不同的疾病实际上会相互促进， 危险的病态环境有趣的是，这种重叠提出了一个重要的新机制， 用于治疗患者的治疗靶点。也就是说，这些共同机制可能对 开发非阿片类药物治疗，用单一药物对这两种疾病都有效。这 这种情况将是双重有利的，因为它可以在早期阶段用作预防性治疗 预防继发性疾病（即疼痛或抑郁）的发展。我们的目标是 测试疼痛和抑郁的共同机制可以用来针对这些假设， 用针对血清素G蛋白偶联受体（GPCR）的新化合物治疗疾病。血清素是一种 脑神经化学物质和5-羟色胺受体是精神疾病中最常见的靶点之一， 最近在慢性疼痛疾病中。大多数使用阿托伐他汀靶向药物的研究都使用了已建立的 神经递质再摄取调节剂，其可以以受体特异性方式具有非预期的作用。的 通过一个受体增加的信号传导可能在一个解剖位置是抗肿瘤的， 另一种是痛觉过敏。为了了解特异性的拮抗或协同作用的潜力， 受体，我们的目标是测试化合物的抗抑郁和镇痛特性，以及在串联 在初始测试期间，共病慢性疼痛和抑郁/焦虑的模型。我们将测试提取物， 从高度多样化的沃茨中现有的和新的微生物收集的馏分和纯化的化合物， 巴拿马和库拉索。从微生物环境中发现天然产物是一个新兴的研究领域。 研究，但已经产生了大量的有趣的和重要的化合物在各种疾病状态。 主要地，研究集中于发现毒性化合物，用于它们作为抗菌、抗微生物、抗病毒和抗微生物的用途。 真菌或抗癌剂。然而，这项提案将检查从微生物中提取的精神活性物质， 本发明涉及化合物及其调节5-羟色胺GPCR、治疗疼痛和抑郁症的能力， 在针对GPCR的体外筛选之后的模型中。这项研究的预期成果将是 鉴定精神活性GPCR的新型配体，并增加对 疼痛和抑郁/焦虑的机制。

PROJECT SUMMARY/ABSTRACT This proposal will use novel marine natural products for the study and treatment of pain, depression, anxiety, and comorbid instances of pain and affective disturbances. Recent evidence demonstrates a significant interaction between chronic pain and depression/anxiety. In particular, chronic pain (e.g. fibromyalgia, chronic lower back pain, painful bladder syndrome) seems to be linked both epidemiologically and biologically with depression/anxiety. In this situation, the separate diseases actually potentiate one another to create an acutely dangerous pathological environment. Interestingly, this overlap presents an important new mechanistic and therapeutic target for the treatment of patients. That is, these common mechanisms might be useful for the development of non-opioid treatments that show efficacy against both diseases with a single agent. This scenario would be doubly advantageous in that it could be used as a prophylactic treatment in the early stages of a single disorder to prevent the development of the secondary disease (i.e. pain or depression). We aim to test the hypothesis that the common mechanisms of pain and depression can be used to target these disorders with novel compounds directed at serotonin G-protein coupled receptors (GPCRs). Serotonin is a brain neurochemical and serotonin receptors are one of the most common targets in psychiatric disease and more recently in chronic pain disorders. Most studies using serotonin-targeting agents have used established neurotransmitter re-uptake modulators, which can have unintended effects in a receptor-specific manner. That is, increased signaling through one receptor may be anti-depressant in one anatomical location but hyperalgesic in another. In order to understand the potential for antagonistic or synergistic actions of specific receptors, we aim to test compounds for both anti-depressant and analgesic properties in tandem as well as in a model of comorbid chronic pain and depression/anxiety during the initial testing. We will be testing extracts, fractions, and purified compounds from existing and new microbial collections from the highly diverse waters of Panama and Curaçao. The discovery of natural products from microbial environments is an emerging field of research but has yielded a large number of interesting and important compounds in a variety of disease states. Predominately, studies have focused on the discovery of toxic compounds for their utility as anti-bacterial, anti- fungal, or anti-cancer agents. This proposal, however, will examine extracts from microbes for psychoactive compounds and their ability to modulate serotonin GPCRs, to treat pain and depression, using in vivo mouse models following in vitro screening against GPCRs. The expected outcomes of this research would be identification of novel ligands for psychoactive GPCRs and an increased understanding of the shared mechanisms of pain and depression/anxiety.