Chemistry and Pharmacology of Iboga Alkaloids

Iboga 生物碱的化学和药理学

基本信息

批准号：
10370433
负责人：
DALIBOR SAMES
金额：
$ 66.25万
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：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370433
关键词：
Absence of pain sensation Abstinence Address Advanced Development Adverse effects Africa African Alcohols Alkaloids Alkenes Amines Analgesics Animals Behavior Behavioral Benzofurans Biological Biological Assay Bioluminescence Biophysics C10 Cardiac Cell Line Central Africa Chemicals Chemistry Clinical Clinical Research Clinical Trials Cocaine Coupling Data Development Diels Alder reaction Disease model Dissociation Docking Drug Addiction Drug Kinetics Drug usage Energy Transfer Engineering Epidemic Europe Exhibits G Protein-Coupled Receptor Signaling GTP-Binding Proteins Goals Human Hydrogen Bonding Iboga Ibogaine In Vitro Indoles Interruption Ion Channel Laboratories Lead Ligands Light Maps Mental disorders Methadone Methods Modeling Molecular Target Morphine Mus Naloxone Native-Born Neuropharmacology Nickel Nicotine Nicotinic Receptors Opiate Addiction Opioid Opioid Receptor Opioid agonist Organic Synthesis Overdose Oxygen Parents Pharmaceutical Preparations Pharmacology Phenols Plant Roots Plants Positioning Attribute Preparation Property Rattus Reaction Receptor Signaling Relapse Replacement Therapy Reporting Research Rodent Rodent Model Role Sedation procedure Self Administration Series Signal Transduction Skeleton Substance Use Disorder Sulfur Synthesis Chemistry System Tail Testing Validation Withdrawal Withdrawal Symptom Yang analog arrestin 2 attenuation benzothiophene beta-arrestin carbene clinical effect craving depressive symptoms design drug craving drug metabolism drug of abuse efficacy evaluation experience experimental study healing in vivo insight kappa opioid receptors monoamine morphine administration neurobehavioral novel novel therapeutics open label opioid use disorder opioid withdrawal overdose death pre-clinical prototype receptor response scaffold sedative side effect substance use substance use treatment tertiary amine

项目摘要

SUMMARY Chemistry and Pharmacology of Iboga Alkaloids Ibogaine is the major psychoactive alkaloid of Tabernanthe iboga, a shrub native to West Central Africa. Since the 1960’s, ibogaine has been known for its ability to interrupt drug addiction. In light of the growing drug use and drug overdose epidemics in the U.S., there is an urgent need for new therapeutics to treat opioid use disorder (OUD) and other substance use disorders (SUDs) - and ibogaine represents an important prototype in this direction. Two recent observational clinical studies confirmed the earlier reports of ibogaine’s effects that include a rapid and long-lasting relief of opioid withdrawal symptoms and cravings, and an increased rate and duration of abstinence in opioid-dependent subjects. The observed response size was comparable to that of methadone replacement therapy. These clinical observations have been replicated in preclinical rodent models of SUDs, including attenuation of self-administration of opioids, cocaine, alcohol and nicotine, mitigation of naloxone-precipitated withdrawal symptoms, and reversal of analgesic tolerance in opioid-dependent animals. The current mechanistic model for ibogaine invokes a role for several key molecular targets, including the a3b4 nicotinic receptor, kappa opioid receptor (KOR), and monoamine transporters. An active metabolite, noribogaine, also makes a significant contribution to the pharmacological effects of ibogaine. We have developed new synthetic methods for de novo synthesis of the iboga alkaloid scaffold, which unlocks unlimited exploration of its pharmacology. We have found that substitution of the indole amine group with other heteroatoms enables accentuation of specific mechanisms of the noribogaine pharmacological profile. The proposed research will focus on benzofuran analogs of noribogaine (oxa-noribogaine) that represent a new class of KOR modulators. Our preliminary results have shown that oxa-noribogaine induces a potent analgesia with no sedative/dissociative side effects in mice, and complete and long-lasting suppression of morphine self- administration in rats, providing a strong rationale for the proposed research. In this application, we will explore the oxa-iboga system in terms of synthetic methods, KOR and opioid receptor pharmacology and signaling, off-target pharmacology, in vivo target validation, and efficacy examination in rat models of OUD. We will also explore the central hypothesis that the benzofuran iboga analogs exhibit an atypical KOR modulator profile that underlies the favorable separation of analgesia and side effects, as well as the efficacy in OUD models. We have assembled an interdisciplinary team with significant experience in synthetic chemistry, computational design, opioid receptor signaling, mouse behavior, and SUD preclinical pharmacology.

概括 IBOGA生物碱的化学和药理学 Ibogaine是Tabernanthe Iboga的主要精神活性生物碱，它是西非西部地区的灌木。自1960年代以来，ibogaine以其中断吸毒的能力而闻名。鉴于生长的药物在美国使用和药物过量发作，迫切需要新的疗法来治疗阿片类药物疾病（OUD）和其他物质使用障碍（SUDS） - ibogaine代表着重要的原型这个方向。最近的两项观察性临床研究证实了伊博加因效应的早期报道，包括阿片类药物戒断症状和渴望的快速和长期缓解，以及增加的速度和阿片类药物依赖性受试者的禁欲持续时间。观察到的响应大小与 Metagadone替代疗法。这些临床观察已在临床前啮齿动物模型中复制肥皂水，包括衰减阿片类药物，可卡因，酒精和尼古丁的衰减，缓解纳洛酮的戒断症状和阿片类动物的镇痛耐受性的逆转。这 ibogaine的当前机械模型唤起了几个关键分子靶标的作用，包括A3B4 烟碱受体，Kappa阿片受体（Kor）和单胺转运蛋白。活跃的代谢物，诺博加因，还为ibogaine的药物作用做出了重大贡献。我们已经开发了新的合成 iboga生物碱支架的从头合成的方法，它解锁了无限探索的方法药理。我们发现，用其他杂原子替代吲哚胺组启用诺里博加因药物概况的特定机制的强调。拟议的研究将专注于代表一类新的KOR调节剂的Noribogaine（Oxa-Noribogaine）的苯并呋喃类似物。我们的初步结果表明，奥斯塔 - 诺里巴加因会影响潜在的镇痛小鼠的镇静/解离副作用，并且对吗啡自我的完全和长期抑制在大鼠的行政管理中，为拟议的研究提供了强有力的理由。在此应用程序中，我们将根据合成方法，KO和阿片类药物受体药理学探索Oxa-biboga系统信号传导，非目标药理学，体内靶验证以及在大鼠模型中有效检查 Oud。我们还将探讨一个中心假设，即苯并呋喃iboga类似物暴露了非典型的kor 调节器的轮廓是镇痛和副作用的有利分离以及有效性的基础在OUD模型中。我们已经组建了一个跨学科团队，具有综合方面的丰富经验化学，计算设计，阿片受体信号，小鼠行为和SUS临床前药理。