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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.

总结