Chemistry and Biology of Mitragynine Alkaloids

帽柱木碱生物碱的化学和生物学

基本信息

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
项目类别：
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

项目摘要

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.

概括帽柱木碱生物碱的化学和生物学！帽柱木碱是一种棒状吲哚生物碱，代表了主要的精神活性成分 Mitragyna spiosa（也称为“kratom”），原产于东南亚的植物。近十年来在美国的崛起，以至于引起了药物管理局的关注尽管 DEA 最初打算对这种植物的两种生物碱进行管制，帽柱木碱和 7-羟基帽柱木碱 (7OH)，被纳入 DEA 管制物质法附表 I 由于公众的强烈反对，最终撤回了这一行动，因此，卡痛叶仍然是一种容易获得的药物。同时，美国和全球大多数其他国家都可以使用“阿片类药物”。卡痛叶生物效应背后的科学仍然知之甚少。解决了对帽柱木碱生物碱进行系统检查的迫切需要，并建立在广泛的基础上我们最近报告了帽柱木碱是一种部分 mu-阿片类药物。具有 G 蛋白偏向信号传导谱的受体 (MOR) 激动剂此外，我们发现帽柱木碱是代谢为 7OH，一种更有效的、G 蛋白偏向的 MOR 激动剂。此外，我们还发现 7OH。对小鼠产生有效的镇痛作用，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类药物模板，可供进一步研究。在此应用中，我们重点关注。从合成方法方面绘制帽柱木碱及其代谢物 7OH 的基础科学，代谢、受体信号传导和药理学特征，通过追求三个综合目标。我们的目标是探索中心假设，即 G 蛋白偏向的 MOR 激动是有利的基础这些目标将是分离帽柱木碱类化合物所表现出的镇痛和副作用。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。