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A Non-Hallucinogenic Psychedelic Analogue with Therapeutic Potential

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A Non-Hallucinogenic Psychedelic Analogue with Therapeutic Potential Article A non-hallucinogenic psychedelic analogue with therapeutic potential https://doi.org/10.1038/s41586-020-3008-z Lindsay P. Cameron1, Robert J. Tombari2, Ju Lu3, Alexander J. Pell2, Zefan Q. Hurley2, Yann Ehinger4, Maxemiliano V. Vargas1, Matthew N. McCarroll5, Jack C. Taylor5, Received: 17 January 2020 Douglas Myers-Turnbull5,6, Taohui Liu3, Bianca Yaghoobi7, Lauren J. Laskowski8, Accepted: 30 October 2020 Emilie I. Anderson8, Guoliang Zhang2, Jayashri Viswanathan2, Brandon M. Brown9, Michelle Tjia3, Lee E. Dunlap2, Zachary T. Rabow10, Oliver Fiehn10, Heike Wulff9, Published online: xx xx xxxx John D. McCorvy8, Pamela J. Lein7, David Kokel5,11, Dorit Ron4, Jamie Peters12,13, Yi Zuo3 & Check for updates David E. Olson2,14,15,16 ✉ 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 efects 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 efects. 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. Ibogaine is the most abundant of the numerous alkaloids produced by that can last for more than 24 hours. Although ibogaine was once sold Tabernanthe iboga5. Although it has not been tested in double-blind, in France as a medicine for the treatment of neuropsychiatric diseases, placebo-controlled clinical trials, anecdotal reports and open-label it was removed from the market owing to its adverse effects1. studies suggest that it can reduce symptoms of drug withdrawal, reduce Although the exact mechanism of action of ibogaine has not yet been drug cravings and prevent relapse1,6. However, the potential of ibogaine fully elucidated, evidence suggests that it might alter addiction-related as a therapeutic is limited by several major issues. First, access to large circuitry by promoting neural plasticity. First, ibogaine has been shown quantities is limited, both by overexploitation of the plant from which it to increase the expression of glial cell-line-derived neurotrophic factor is derived and by the lack of a scalable, enantioselective, total synthesis6. (GDNF) in the ventral tegmental area, and infusion of ibogaine into this Currently, there are only three synthetic routes to racemic ibogaine, region of the midbrain reduces alcohol-seeking behaviour in rodents3. with longest linear sequences of between 9 and 16 steps and overall A more recent study demonstrated that ibogaine affects brain-derived yields that range from 0.1 to 4.8%6. Second, the safety profile of ibogaine neurotrophic factor and GDNF signalling in several brain regions that is unacceptable. It is very non-polar, which leads to its accumulation are implicated in the behavioural effects of addictive drugs4. Recently, in adipose tissue7 and contributes to its known cardiotoxicity through we demonstrated that noribogaine—an active metabolite of ibogaine12— the inhibition of hERG potassium channels8,9. Several deaths have been is a potent psychoplastogen13 that increases the complexity of cortical linked to the cardiotoxicity of ibogaine10,11, and it induces hallucinations neuron dendritic arbors14. Other psychoplastogens—such as lysergic 1Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA. 2Department of Chemistry, University of California, Davis, Davis, CA, USA. 3Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA. 4Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. 5Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA. 6Quantitative Biosciences Consortium, University of California, San Francisco, San Francisco, CA, USA. 7Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA. 8Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA. 9Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, USA. 10West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA. 11Department of Physiology, University of California, San Francisco, San Francisco, CA, USA. 12Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. 13Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. 14Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA. 15Center for Neuroscience, University of California, Davis, Davis, CA, USA. 16Delix Therapeutics, Inc., Palo Alto, CA, USA. ✉e-mail: [email protected] Nature | www.nature.com | 1 Article acid diethylamide (LSD) and psilocin (the active metabolite of psilo- psychoplastogenic performance to ibogaine despite its simplified cybin)—have also been shown in anecdotal and open-label studies to chemical structure. We therefore prioritized IBG for further develop- decrease drug use in the clinic, similar to ibogaine15. We suggest that ment, because we reasoned that its reduced lipophilicity (calculated the ability of psychoplastogens to promote structural and functional logarithm of partition coefficient, clogP = 2.61) relative to that of ibo- neural plasticity in addiction-related circuitry might explain their gaine (clogP = 4.27) would make formulation less challenging and would ability to reduce drug-seeking behaviour for weeks to months after a also reduce the potential for cardiotoxicity, as lipophilicity is a known single administration. Moreover, by modifying neural circuitry rather contributing factor to hERG channel inhibition. The attractiveness of than simply blocking the targets of a particular addictive substance, IBG as a potential therapeutic was underscored by its improved central psychoplastogens such as ibogaine could have the potential for broad nervous system (CNS) multiparameter optimization (MPO) score18 use as anti-addictive agents, applicable to the treatment of addiction (MPO IBG = 5.2; MPO ibogaine = 3.8; optimal MPO = 6.0) coupled with to various substances. the fact that it can be synthesized in a single step. To develop simplified, and potentially safer, analogues of ibogaine we first needed to understand which of its structural features were critical for its psychoplastogenic effects. Our approach was similar to seminal TBG is a safer, non-hallucinogenic 5-HT2A agonist function-oriented synthesis studies of the structurally complex marine The structure of IBG is similar to that of the potent hallucino- 16 natural product bryostatin 1 . Here we report our efforts to engineer gen and serotonin 2A receptor (5-HT2A) agonist 5-methoxy- simplified analogues of iboga alkaloids (ibogalogs) that lack the toxic- N,N-dimethyltryptamine (5-MeO-DMT). Previous structure–activity ity and hallucinogenic effects of ibogaine but maintain its behavioural relationship studies demonstrated that, unlike 5-MeO-DMT and other effects in rodent models of drug self-administration and relapse. known hallucinogens, 6-MeO-DMT did not substitute for the hallucino- gen 2,5-dimethoxy-4-methylamphetamine at any dose in rodents that were trained to discriminate this compound from saline19. Moreover, Function-oriented synthesis of ibogalogs our group has previously shown that 6-MeO-DMT does not produce a Characteristic structural features of ibogaine include an indole, a head-twitch response20—a well-established rodent behavioural proxy 21 7-membered tetrahydroazepine and a bicyclic isoquinuclidine (Fig. 1). for hallucinations induced by 5-HT2A agonists . We therefore synthe- We reasoned that systematic deletion of these key structural elements sized the 6-methoxyindole-fused tetrahydroazepine 18. Because 18 would reveal the essential features of the psychoplastogenic pharma- resembles the iboga alkaloid tabernanthine, we refer to this compound cophore of ibogaine. By adapting previously developed chemistry17, we as tabernanthalog (TBG). Like IBG, TBG can be synthesized in a single were able to access a series of isoquinuclidine-containing compounds step, enabling large quantities (more than 1 g) to be rapidly produced. (8–11) that lacked the tetrahydroazepine and/or indole moieties that To evaluate the hallucinogenic potential of IBG and TBG, we tested are characteristic of ibogaine (Extended Data Fig. 1a). Ibogalog 8a them in the head-twitch response assay
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