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伊博加因是 Tabernanthe iboga 的主要精神活性生物碱，Tabernanthe iboga 是一种原产于中非西部的灌木。自 20 世纪 60 年代以来，随着毒品的增长，伊博加因以其戒断毒瘾的能力而闻名。在美国，阿片类药物的使用和药物过量流行，迫切需要新的疗法来治疗阿片类药物的使用障碍（OUD）和其他物质使用障碍（SUD） - 伊博加因代表了一个重要的原型最近的两项观察性临床研究证实了伊博加因的作用的早期报告。包括快速、持久地缓解阿片类药物戒断症状和渴望，以及增加戒断率和观察到的阿片类药物依赖受试者的戒断持续时间与戒断时间相当。美沙酮替代疗法已在临床前啮齿动物模型中得到重复。 SUD 的使用，包括减少阿片类药物、可卡因、酒精和尼古丁的自我给药，减轻纳洛酮诱发戒断症状，并逆转阿片类药物依赖性动物的镇痛耐受性。目前伊博加因的机制模型调用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) 和单胺转运蛋白一种活性代谢物 noribogaine，我们还开发了新的合成物，对伊博加因的药理作用做出了重大贡献。 iboga生物碱支架的从头合成方法，开启了对其的无限探索我们发现用其他杂原子取代吲哚胺基团可以实现药理学。拟议的研究将强调降伊波加因药理学特征的具体机制。重点关注降伊博加因 (oxa-noribogaine) 的苯并呋喃类似物，它代表了一类新的 KOR 调节剂。我们的初步结果表明，ox-noribogaine 可诱导有效的镇痛作用，且无需对小鼠产生镇静/解离副作用，并完全且持久地抑制吗啡自我在大鼠中给药，为拟议的研究提供了强有力的理由，我们将在本申请中进行。从合成方法、KOR 和阿片受体药理学方面探索 oxa-iboga 系统大鼠模型中的信号传导、脱靶药理学、体内靶标验证和功效检查我们还将探讨苯并呋喃 iboga 类似物表现出非典型 KOR 的中心假设。调节剂概况是镇痛和副作用以及功效良好分离的基础我们组建了一支在合成领域拥有丰富经验的跨学科团队。化学、计算设计、阿片受体信号传导、小鼠行为和 SUD 临床前药理。