Chemistry and Pharmacology of Iboga Alkaloids

Iboga 生物碱的化学和药理学

• 批准号: 10594417
• 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
• 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/10594417
• 关键词: ARRB2; 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; 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; Plants; Positioning Attribute; 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; analog; attenuation; benzothiophene; carbene; clinical effect; craving; depressive symptoms; design; drug craving; drug metabolism; drug of abuse; efficacy evaluation; enantiomer; experience; experimental study; healing; in vivo; insight; kappa opioid receptors; monoamine; morphine administration; neurobehavioral; new chemical entity; novel; novel therapeutics; open label; opioid use disorder; opioid withdrawal; overdose death; pharmacologic; pre-clinical; prototype; receptor; response; scaffold; sedative; side effect; substance use; substance use treatment; tertiary amine

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.

总结 伊博加生物碱的化学和药理学 伊博沙是Tabernanthe iboga的主要精神活性生物碱，Tabernanthe iboga是一种原产于中西部非洲的灌木。 自20世纪60年代以来，伊波替尼因其中断药物成瘾的能力而闻名。鉴于越来越多的毒品 吸毒和药物过量的流行，迫切需要新的治疗方法来治疗阿片类药物的使用 疾病（OUD）和其他物质使用障碍（SUDs）-和iboclavin代表了一个重要的原型， 这个方向。最近的两项观察性临床研究证实了早期关于伊波替尼作用的报道， 包括阿片类戒断症状和渴望的快速和持久的缓解， 阿片类药物依赖受试者的戒断持续时间。观察到的响应大小与 美沙酮替代疗法这些临床观察结果已在临床前啮齿动物模型中得到复制 包括减少阿片类药物、可卡因、酒精和尼古丁的自我给药， 纳洛酮诱发的戒断症状，以及阿片类药物依赖动物的镇痛耐受性逆转。的 目前的ibo作用机制模型涉及几个关键分子靶点，包括a3 b4 烟碱受体、κ阿片受体（KOR）和单胺转运蛋白。一种活性代谢物，诺瑞波替尼， 也对伊波替尼的药理学作用有显著贡献。我们开发了一种新的合成 方法从头合成的iboga生物碱支架，这解锁了无限的探索， 药理学我们发现用其他杂原子取代吲哚胺基团能够 增强了诺瑞波替尼药理学特性的特定机制。拟议的研究将 重点关注代表一类新的KOR调节剂的诺立波替尼的苯并呋喃类似物（氧杂-诺立波替尼）。 我们的初步研究结果表明，oxa-noriboylate诱导有效的镇痛作用， 镇静/解离的副作用，以及吗啡自身 在大鼠中施用，为所提出的研究提供了强有力的理由。在这个应用程序中，我们将 从合成方法、KOR和阿片受体药理学方面探讨oxa-iboga系统， 信号传导、脱靶药理学、体内靶向验证和大鼠模型中的功效检查 OUD。我们还将探讨中心假设，苯并呋喃iboga类似物表现出非典型的KOR 调节剂概况，其是镇痛和副作用的有利分离的基础， 在OUD模型中。我们组建了一支跨学科的团队，在合成化学方面具有丰富的经验。 化学、计算设计、阿片受体信号传导、小鼠行为和SUD临床前 药理学