Chemistry and Pharmacology of Iboga Alkaloids

摘要 IBOGA生物碱的化学和药理作用 Ibogaine是原产于中非西部的灌木Tabernanthe iboga的主要精神活性生物碱。 自20世纪60年代的S以来，伊波加因一直以其戒除毒瘾的能力而闻名。鉴于毒品的不断增长 在美国，药物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(SOD)-伊波甘代表了 这个方向。最近的两项观察性临床研究证实了早先关于伊博加因影响的报道 包括迅速和长期缓解阿片类药物戒断症状和渴望，以及提高戒断率和 阿片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。这些临床观察已经在临床前啮齿动物模型中重复。 肥皂水，包括减少阿片类药物、可卡因、酒精和尼古丁的自我给药，缓解 纳洛酮催促的戒断症状和阿片依赖动物的止痛耐受逆转。这个 目前ibogaine的机制模型调用了包括a3b4在内的几个关键分子靶点的作用。 烟碱受体、kappa阿片受体(KOR)和单胺转运体。一种活跃的代谢物，诺里博甘， 也对伊波甘的药理作用做出了重大贡献。我们开发了一种新的合成材料 Iboga生物碱支架的从头合成方法，开启了对其无限探索的大门 药理学。我们已经发现，用其他杂原子取代吲哚胺基能够 强调诺利波建药理作用的具体机制。拟议的研究将 重点关注代表一类新的KOR调节剂的诺里博甘(oxa-noribogaine)的苯并呋喃类似物。 我们的初步研究结果表明，奥沙诺明对NO有很强的镇痛作用。 小鼠的镇静/解离副作用，以及对吗啡自身的完全和持久的抑制 为拟议的研究提供了强有力的理论基础。在此应用程序中，我们将 从合成方法、KOR和阿片受体药理及药理作用等方面探讨oxa-iboga系统 信号转导、靶外药理学、体内靶点验证和药效检测 奥德。我们还将探索中心假设，即苯并呋喃iboga类似物表现出非典型的KOR 作为止痛和副作用以及疗效良好分离的基础的调节剂配置文件 在OUD模型中。我们组建了一支跨学科的团队，在合成方面拥有丰富的经验 化学、计算设计、阿片受体信号、小鼠行为和SUD临床前 药理学。

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.