Chemistry and Biology of Mitragynine Alkaloids

帽柱木碱生物碱的化学和生物学

• 批准号: 10203899
• 负责人: Susruta Majumdar
• 金额: $ 60.12万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203899
• 关键词: Absence of pain sensation; Address; Adopted; Adverse effects; Affinity; Alkaloids; Alternative Medicine; Analgesics; Anxiety; Attention; Basic Science; Biological; Biological Assay; Biology; Bioluminescence; Brain; C10; Cell Line; Chemicals; Chemistry; Clinical; Computer Assisted; Constipation; Country; Data; Development; Disease; Docking; Drug Design; Drug Kinetics; Energy Transfer; Exhibits; Future; G Protein-Coupled Receptor Signaling; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Human; In Vitro; Indigenous; Indole Alkaloids; Indoles; Investigation; Lead; Ligands; Maps; Metabolic; Metabolism; Methods; Mitragyna; Modeling; Molecular; Morphine; Mus; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Opioid agonist; Organic Synthesis; Pain; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Plant Leaves; Plant alkaloid; Plants; Plasma; Play; Positioning Attribute; Property; Receptor Activation; Receptor Signaling; Recording of previous events; Reporting; Research; Role; Schedule; Series; Signal Transduction; Site; Southeastern Asia; Structure; Syndrome; Synthesis Chemistry; Tail; Testing; Therapeutic; Time; United States; Ventilatory Depression; analog; arrestin 2; beta-arrestin; computational chemistry; design; drug action; experience; functional group; in vivo; in vivo evaluation; insight; mu opioid receptors; next generation; opioid use; pharmacophore; radioligand; receptor; recruit; scaffold; side effect; treatment-resistant depression

SUMMARY Chemistry and Biology of Mitragynine Alkaloids ! Mitragynine is a corynanthe-type indole alkaloid representing the major psychoactive constituent of Mitragyna speciosa (also known as “kratom”), a plant native to Southeast Asia. The use of kratom has been on the rise in the U.S. in the last decade, to such an extent that it attracted the attention of the Drug Enforcement Administration (DEA). Despite the initial intent by the DEA to place two alkaloids of this plant, mitragynine and 7-hydroxymitragynine (7OH), into Schedule I of the Control Substance Act, the DEA eventually withdrew this action following dramatic opposition from the public. Thus, kratom remains a readily available “opioid material” in the U.S. and most other countries worldwide. At the same time, the basic science underlying the biological effects of kratom remains poorly understood. The proposed research addresses an urgent need for a systematic examination of mitragynine alkaloids and builds on extensive preliminary results generated by the PIs. We have recently reported that mitragynine is a partial mu-opioid receptor (MOR) agonist with a G protein-biased signaling profile. In addition, we have found that mitragynine is metabolized to 7OH, a more potent, G protein-biased MOR agonist. Furthermore, we have shown that 7OH induces potent analgesia in mice without respiratory depression and constipation side effects, and thus, represents an attractive atypical opioid template for further investigations. In this application, we focus on mapping the basic science of mitragynine and its metabolite 7OH in terms of synthetic methods, metabolism, receptor signaling and pharmacological profile,!by pursuing three integrated aims. Moreover, we aim to explore the central hypothesis that G protein-biased MOR agonism underlies the favorable separation of analgesia and side effects exhibited by mitragynine-type compounds. These goals will be accomplished by an interdisciplinary team with significant experience in synthetic and computational chemistry, opioid receptor signaling, and in vitro and in vivo pharmacology.

摘要 三叶草碱类生物碱的化学和生物学研究 好了！ 米特拉吉宁是一种洋参碱型吲哚生物碱，代表了木犀草素的主要精神活性成分 原产于东南亚的一种植物--光叶菊属。KrATOM的使用一直是 关于美国在过去十年中的崛起，以至于引起了毒品的注意 执行管理局(DEA)。尽管DEA最初打算放置这种植物的两种生物碱， 将三氢呋喃和7-羟基三氢呋喃(7OH)纳入《控制物质法》附表一，即DEA 在遭到公众的强烈反对后，最终撤回了这一行动。因此，KrATOM仍然是一个现成的 在美国和世界上大多数其他国家都有“阿片类物质”。同时，基本的 KrATOM生物效应背后的科学仍然知之甚少。拟议的研究 解决了对三叶生物碱进行系统检查的迫切需要，并建立在广泛的 PIS生成的初步结果。我们最近报道了米拉吉宁是一种部分阿片类药物。 受体(MOR)激动剂，具有G蛋白偏向的信号转导。此外，我们还发现，米曲吉宁是 代谢到7OH，一种更有效的偏重于G蛋白的MOR激动剂。此外，我们已经证明了7OH 对小鼠有很强的镇痛作用，没有呼吸抑制和便秘副作用，因此， 代表了一个有吸引力的非典型阿片类药物模板，用于进一步研究。在本应用程序中，我们重点介绍 绘制合成方法方面的米曲尼宁及其代谢物7OH的基础科学图， 代谢、受体信号和药理特性，！追求三个综合目标。此外， 我们的目标是探索中心假设，即G蛋白偏向的MOR激动症是有利的 三氢呋喃类化合物的止痛和副作用的分离。这些目标将是 由在合成和计算领域拥有丰富经验的跨学科团队完成 化学、阿片受体信号、体外和体内药理学。