The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs
TL;DR: 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 and historical context for the discoveries of the past decade is provided.
About: This article is published in Natural Product Reports.The article was published on 2021-03-04. It has received 28 citations till now.
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TL;DR: 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.
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.
134 citations
20 Jul 2021
TL;DR: Tabernanthalog (TBG) appears to have long-lasting therapeutic effects in preclinical models relevant to alcohol and opioid addiction, and 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 as discussed by the authors.
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.
14 citations
TL;DR: In this paper, a ring-opening functionalization of a tertiary amine was proposed to introduce desired functionalities in the context of alkaloids reorganization, and applied in the transformation of securinega, iboga, and sarpagine alkaloid to neosecurinega and chippiine/dippinine, respectively.
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.
12 citations
25 Mar 2021
7 citations
TL;DR: The recent advances in divergent synthetic approaches such as complexity-to-diversity (Ctd) and biomimetic strategies for the generation of structurally complex and diverse indole-based natural product and natural product-like small-molecule libraries are reviewed.
Abstract: Considering the potential bioactivities of natural product and natural product-like compounds with highly complex and diverse structures, the screening of collections and small-molecule libraries for high-throughput screening (HTS) and high-content screening (HCS) has emerged as a powerful tool in the development of novel therapeutic agents. Herein, we review the recent advances in divergent synthetic approaches such as complexity-to-diversity (Ctd) and biomimetic strategies for the generation of structurally complex and diverse indole-based natural product and natural product-like small-molecule libraries.
5 citations
References
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TL;DR: In this paper, the total synthesis of amaryllidaceae alkaloids has been studied using radical cyclization reactions in total syntheses of naturally occurring indole alkaloid.
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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TL;DR: Improved transporters that can deliver agents in a superior fashion compared with naturally occurring cell-penetrating peptides and that can be synthesized in a practical and step-economical fashion are generated.
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761 citations
TL;DR: Highly enantioenriched indolizinone and quinoliz inone products are obtained in the thiourea-catalyzed cyclization of tryptamine-derived hydroxylactams.
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.
450 citations
TL;DR: It is reported that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo.
436 citations