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Journal ArticleDOI: 10.1039/D0NP00033G

The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs

04 Mar 2021-Natural Product Reports (The Royal Society of Chemistry)-Vol. 38, Iss: 2, pp 307-329
Abstract: Covering: 2000 up to 2020 Few classes of natural products have inspired as many chemists and biologists as have the iboga alkaloids. This family of monoterpenoid indole alkaloids includes the anti-addictive compound ibogaine as well as catharanthine, a precursor to the chemotherapeutic vinblastine. Despite being known for over 120 years, these small molecules continue to challenge our assumptions about biosynthetic pathways, catalyze our creativity for constructing complex architectures, and embolden new approaches for treating mental illness. This review will cover recent advances in both the biosynthesis and chemical synthesis of iboga alkaloids as well as their use as next-generation neurotherapeutics. Whenever appropriate, we provide historical context for the discoveries of the past decade and indicate areas that have yet to be resolved. While significant progress regarding their chemistry and pharmacology has been made since the 1960s, it is clear that the iboga alkaloids will continue to stoke scientific innovation for years to come.

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Citations
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6 results found


Open accessJournal ArticleDOI: 10.1038/S41586-020-3008-Z
Lindsay P. Cameron1, Robert J. Tombari1, Ju Lu2, Alexander J. Pell1  +25 moreInstitutions (5)
21 Jan 2021-Nature
Abstract: The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

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Topics: Ibogaine (58%)

35 Citations


Open accessJournal ArticleDOI: 10.1021/ACSOMEGA.1C00745
24 Jun 2021-
Abstract: Iboga alkaloids are a group of monoterpenoid indole alkaloids with promising and intriguing biological activities. Ibogaine is the representative member of the series and has become widely known as a potent atypical psychedelic with promising effects to treat substance use disorder. Nowadays, an efficient and scalable enantioselective total synthesis of ibogaine and related iboga alkaloids is still lacking, so direct extraction from natural sources or semi-synthetic schemes are the methods of choice to obtain them in a preparative scale. In particular, ibogaine can be obtained either by a low yielding direct isolation from Tabernanthe iboga or using a semi-synthetic procedure from voacangine, an iboga alkaloid occurring in a higher yield in the root bark of Voacanga africana. In this work, we describe an optimized process to obtain voacangine from V. africana root bark as a precursor of the iboga scaffold. Using a direct acetone-based extraction procedure (0.5 kg of root bark), voacangine was isolated in ∼0.8% of root bark dried weight, while the major alkaloids isolated from the bark were identified as iboga-vobasinyl dimers (∼3.7%) such as voacamine and voacamidine. Since these alkaloids contain the voacangine moiety in their structure, the cleavage of the dimers was further optimized, affording an extra amount of voacangine in ∼50% isolated molar yield. In this manner, the total amount of voacangine obtained by application of the whole procedure to the plant material (extraction and dimer cleavage) could almost duplicate the content originally found in the root bark.

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Topics: Voacangine (77%), Iboga alkaloid (76%), Voacanga africana (70%) ... read more

2 Citations


Open accessJournal ArticleDOI: 10.1021/JACS.1C10205
Hyeonggeun Lim1, Sikwang Seong1, Youyoung Kim1, Sangwon Seo1  +1 moreInstitutions (1)
Abstract: Biosynthetic processes often involve reorganization of one family of natural products to another. Chemical emulation of nature's rearrangement-based structural diversification strategy would enable the conversion of readily available natural products to other value-added secondary metabolites. However, the development of a chemical method that can be universally applied to structurally diverse natural products is nontrivial. Key to the successful reorganization of complex molecules is a versatile and mild bond-cleaving method that correctly places desired functionality, facilitating the target synthesis. Here, we report a ring-opening functionalization of a tertiary amine that can introduce desired functionalities in the context of alkaloids reorganization. The semistability of the difluoromethylated ammonium salt, accessed by the reaction of tertiary amine and in situ generated difluorocarbene, enabled the attack at the α-position by various external nucleophiles. The utility and generality of the method is highlighted by its applications in the transformation of securinega, iboga, and sarpagine alkaloids to neosecurinega, chippiine/dippinine, and vobasine-type bisindole alkaloids, respectively. During the course of these biosynthetically inspired reorganizations, we could explore chemical reactivities of biogenetically relevant precursors.

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Topics: Tertiary amine (62%)

Open accessJournal ArticleDOI: 10.1177/26331055211033847
Jamie Peters1, David E. Olson2Institutions (2)
20 Jul 2021-
Abstract: Addiction is best described as a disorder of maladaptive neuroplasticity involving the simultaneous strengthening of reward circuitry that drives compulsive drug seeking and weakening of circuits involved in executive control over harmful behaviors. Psychedelics have shown great promise for treating addiction, with many people attributing their therapeutic effects to insights gained while under the influence of the drug. However, psychedelics are also potent psychoplastogens-molecules capable of rapidly re-wiring the adult brain. The advent of non-hallucinogenic psychoplastogens with anti-addictive properties raises the intriguing possibility that hallucinations might not be necessary for all therapeutic effects of psychedelic-based medicines, so long as the underlying pathological neural circuitry can be remedied. One of these non-hallucinogenic psychoplastogens, tabernanthalog (TBG), appears to have long-lasting therapeutic effects in preclinical models relevant to alcohol and opioid addiction. Here, we discuss the implications of these results for the development of addiction treatments, as well as the next steps for advancing TBG and related non-hallucinogenic psychoplastogens as addiction therapeutics.

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Topics: Addiction (57%)

Journal ArticleDOI: 10.1038/D41586-020-03404-Z
01 Jan 2021-Nature
Abstract: An analogue of the psychedelic drug ibogaine has been developed. The analogue mirrors ibogaine’s ability to treat addiction and depression in animal models, has fewer side effects and is much simpler to synthesize. A safer analogue of the psychedelic compound ibogaine.

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Topics: Ibogaine (58%), Psychedelic drug (56%)

References
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173 results found


01 Jan 1991-
Abstract: Chapter headings. Carbon-13 and proton NMR shift assignments and physical constants of diterpenoid alkaloids. Supercritical fluid extraction of alkaloids. Recent advances in the total synthesis of amaryllidaceae alkaloids. Applications of radical cyclization reactions in total syntheses of naturally occurring indole alkaloids.

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1,262 Citations


Journal ArticleDOI: 10.1021/AR700155P
Abstract: This Account provides an overview and examples of function-oriented synthesis (FOS) and its increasingly important role in producing therapeutic leads that can be made in a step-economical fashion. Biologically active natural product leads often suffer from several deficiencies. Many are scarce or difficult to obtain from natural sources. Often, they are highly complex molecules and thus not amenable to a practical synthesis that would impact supply. Most are not optimally suitable for human therapeutic use. The central principle of FOS is that the function of a biologically active lead structure can be recapitulated, tuned, or greatly enhanced with simpler scaffolds designed for ease of synthesis and also synthetic innovation. This approach can provide practical access to new (designed) structures with novel activities while at the same time allowing for synthetic innovation by target design. This FOS approach has been applied to a number of therapeutically important natural product leads. For example, b...

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856 Citations


Journal ArticleDOI: 10.1039/B512615K
Sarah E. O'Connor1, Justin J. Maresh1Institutions (1)
Abstract: Covering: up to 2006 Monoterpene indole alkaloids exhibit a diverse array of structures and biological activities. The biosynthetic pathways for several representative terpene indole alkaloids are described in detail.

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Topics: Indole test (61%), Strictosidine (53%), Strictosidine synthase (51%)

647 Citations


Journal ArticleDOI: 10.1021/JA076179W
Abstract: Highly enantioenriched indolizinone and quinolizinone products are obtained in the thiourea-catalyzed cyclization of tryptamine-derived hydroxylactams. Substituent and counterion effect studies point to a novel mechanism of catalysis involving rate-limiting anion abstraction and binding by the thiourea.

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Topics: Anion binding (60%), Counterion (52%)

413 Citations


Journal ArticleDOI: 10.1021/OL035355C
09 Sep 2003-Organic Letters
Abstract: [reaction: see text] A general and efficient copper-catalyzed method for the amidation of vinyl bromides and iodides has been developed. This protocol uses a combination of 5 mol % copper iodide and 20 mol % N,N'-dimethyl ethylenediamine. Substrates bearing ester, silyl ether, and amino groups were successfully coupled under the reaction conditions. The double bond geometry of the vinyl halides was retained under the reaction conditions.

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Topics: Silyl ether (55%), Double bond (52%), Ethylenediamine (51%)

349 Citations


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