Design and Synthesis of Collybolide Probes for Kappa-Opioid Receptor

Kappa-阿片受体激活剂探针的设计与合成 摘要： 虽然吗啡等非鸦片类镇痛剂对剧烈疼痛有效，但由于以下原因，其使用受到限制 不良副作用，如呼吸抑制、身体依赖、心理成瘾、滥用 责任和瘙痒。研究表明，选择性kappa-阿片受体(KOR)激动剂偏向于G-受体。 蛋白质信号转导可能成为治疗疼痛且副作用减少的新疗法。破译结构性的 通过新的化学探针对KOR选择性的基本要求是开发的第一步 有选择性和有偏见的KOR配体。在寻找新的KOR化学探测器的过程中，我们发现了胶原胺，一种 从蘑菇中提取的无氮倍半萜天然产物 具有体内止痛和止痒活性的选择性KOR激动剂。Collybolide具有呋喃-δ-内酯核心 与Salvinorin A相似，但与后者的不同之处在于表现出功能选择性以及50- 在阻断非组胺介导的瘙痒方面的效力提高了一倍。这项研究计划的长期目标是 开发副作用减少的KOR类止痛药和止痒药。这个项目的目标是 用于识别选择性KOR配体和偏置KOR配体的新型胶体化合物探针的研制 体内使用的药理学概况。我们的假设是胶胞菌素的合理结构多样化 将提供新的探针，以获得可能导致有效开发的重要结构信息 减少副作用的治疗瘙痒和疼痛的疗法。在强劲的初步数据的指引下， 这一假设将通过追求以下具体目标来检验：1)综合和评估第一- 用于识别选择性和偏置KOR配体的新一代胶体探针；2)设计、合成和 对具有类药物特性的优化的Colybolide类似物进行体内评估，以确定潜在的止痛剂和 副作用减少的止痒剂。建议的研究将由具有高度资质的 在天然产物分离、有机合成和药物方面拥有协同专业知识的研究团队 化学以及药理学、神经科学、计算对接和蛋白质结晶。这个 在这一应用中的研究将全面考察胶原素和 有望产生一组选择性和偏向的或配体，有可能成为先导药物 止痒止痛的候选药物，副作用减少。此外，NIMH-PDSP的高通量筛查 针对50个中枢神经系统受体可以发现新的靶点，可以进一步优化以探索新的治疗方法 机遇。

Design and Synthesis of Collybolide Probes for Kappa-Opioid Receptor Abstract: While the mu-opiate analgesics such as morphine are effective for severe pain, their use is limited due to unwanted side effects such as respiratory depression, physical dependence, psychological addiction, abuse liability and itching. Studies suggest that selective kappa-opioid receptor (KOR) agonists biased towards G- protein signaling could be novel therapeutics to treat pain with reduced side effects. Deciphering the structural requirements essential for KOR selectivity through novel chemical probes is the first step in developing selective- and biased-KOR ligands. In the quest for new KOR chemical probes, we identified collybolide, a non-nitrogenous sesquiterpene natural product extracted from the mushroom Collybia maculata as a highly selective KOR agonist having in vivo analgesic and antipruritic activity. Collybolide has a furyl-δ-lactone core similar to that of salvinorin A, however differs from the latter in exhibiting functional selectivity along with a 50- fold higher potency in blocking non-histamine-mediated itch. The long-term goal of this research program is to develop KOR based analgesics and anti-pruritic drugs with reduced side effects. The objective of this project is the development of novel collybolide probes for identifying selective- and biased-KOR ligands with desirable pharmacological profiles for use in vivo. Our hypothesis is that rational structural diversification of collybolide will provide novel probes to gain important structural information that could lead to the development of effective therapeutics for the treatment of pruritus and pain with reduced side effects. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following specific aims: 1) Synthesis and evaluation of first- generation collybolide probes for identifying selective-and biased KOR ligands; 2) Design, synthesis and in vivo evaluation of optimized collybolide analogues with drug-like properties to identify potential analgesics and anti-pruritus agents with reduced side-effects. The proposed research will be performed by a highly qualified team of researchers having synergistic expertise in natural products isolation, organic synthesis, and medicinal chemistry as well as in pharmacology, neuroscience, computational docking, and protein crystallization. The studies in this application will comprehensively examine the structure–activity relationships of collybolide and are expected to yield a set of selective- and biased-OR ligands with the potential of becoming lead drug candidates for itch and pain with reduced side effects. Further, high-throughput screening at the NIMH-PDSP against 50 CNS receptors could find new hits, which could be optimized further to explore new therapeutic opportunities.