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：
9765285
负责人：
Susruta Majumdar
金额：
$ 59.62万
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/9765285
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 Drug effect disorder 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 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 Mitragynine生物碱的化学和生物学呢 Mitragynine是一种Corynanthe型吲哚生物碱，代表了主要的精神活性宪法 Mitragyna Speciosa（也称为“ kratom”），这是东南亚本地的植物。 kratom的使用已经在过去十年中，美国的兴起，以至于吸引了该药物的注意力执法局（DEA）。尽管DEA最初意图放置该植物的两种生物碱，但 Mitragynine和7-羟基甲酸（7OH），进入控制物质法的附表I，DEA 在公众的戏剧性反对之后，甚至撤回了这一诉讼。那，Kratom仍然很容易在美国和全球大多数其他国家 /地区可用的“阿片类药物材料”。同时，基本 KRATOM生物学作用的基础科学知识仍然很少。拟议的研究迫切需要对Mitragynine生物碱进行系统检查，并建立在广泛的基础上 PIS产生的初步结果。我们最近报道说，米特拉吉宁是一种部分静脉 - 阿片类药物具有G蛋白偏置信号谱的受体（MOR）激动剂。此外，我们发现Mitragynine是代谢为7OH，具有更大潜力的G蛋白偏向MOR激动剂。此外，我们已经证明了7OH 在没有呼吸抑郁和便秘副作用的小鼠中诱导潜在的镇痛，因此代表一个有吸引力的非典型阿片类型模板，用于进一步研究。在此应用中，我们专注于根据合成方法，绘制Mitragynine及其代谢物7OH的基础科学，代谢，受体信号传导和药物概况，通过追求三个综合目的。而且，我们的目的是探讨蛋白质偏向动力学的中心假设是有利的镇痛和副作用的分离，通过mitragynine型化合物暴露出来。这些目标将是由跨学科团队完成的合成和计算方面经验丰富的团队化学，阿片受体信号传导以及体外和体内药理学。