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.

总结 Mitragynine生物碱的化学和生物学 ! Mitragynine是一种紫堇型吲哚生物碱，代表了 Mitragyna speciosa（也被称为“kratom”），原产于东南亚的植物。kratom的使用已经 在过去的十年里，美国的崛起，以至于它吸引了药物的注意力。 执法管理局（DEA）。尽管DEA最初打算将这种植物的两种生物碱， mitragynine和7-hydroxymitragynine（7 OH），列入管制物质法（DEA）附表I 最终在公众强烈反对下撤回了这一行动。因此，Kratom仍然是一个容易 在美国和世界上大多数其他国家都有可用的“阿片类物质”。同时，基本 对kratom生物效应的科学基础仍然知之甚少。拟议研究 解决了迫切需要一个系统的检查mitragynine生物碱，并建立在广泛的 PI生成的初步结果。我们最近报道，mitragynine是一个部分μ阿片类药物 受体（莫尔）激动剂，具有G蛋白偏向的信号传导特征。此外，我们发现mitragynine是 代谢为7 OH，一种更有效的G蛋白偏向性莫尔激动剂。此外，我们还证明了7 OH 在小鼠中诱导有效的镇痛而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样物质模板，用于进一步研究。在本应用程序中，我们重点关注 从合成方法方面对mitragynine及其代谢产物7 OH的基础科学进行了测绘， 代谢，受体信号和药理学概况，！实现三个综合目标。此外，委员会认为， 我们的目标是探索核心假设，即G蛋白偏向的莫尔激动作用是有利的基础 分离由mitragynine型化合物表现出的镇痛和副作用。这些目标将是 由在合成和计算方面具有丰富经验的跨学科团队完成 化学、阿片受体信号传导以及体外和体内药理学。