Efficient and modular synthesis of ibogaine and related alkaloids.
Rishab N Iyer, David Favela, Andras Domokos, Guoliang Zhang, Arabo A Avanes, Samuel J Carter, Andrian G Basargin, Alexis R Davis, Dean J Tantillo, David E Olson
Nature chemistry March 1, 2025 DOI: 10.1038/s41557-024-01714-7 via PubMed
Summary
AI-generated from the abstractA new chemical method produces ibogaine in seven steps from pyridine, enabling gram-scale synthesis. This approach also creates three additional iboga alkaloids, the unnatural enantiomer (+)-ibogaine, and four analogues. Biological tests show that (+)-ibogaine does not affect cortical neuron growth like natural ibogaine, while (-)-10-fluoroibogamine strongly promotes neuron growth and potently modulates the serotonin transporter. The work provides a platform for making iboga alkaloids and related compounds for further study, supporting research into their therapeutic potential for addiction and other neuropsychiatric conditions.
Study at a glance
| Characteristics | Chemical synthesis and biological testing Peer reviewed |
|---|---|
| Topics | Ibogaine |
| Keywords | Natural compound Related alkaloids --10-fluoroibogamine Important compounds |
| Citations | 22 |
| Key finding | A gram-scale, seven-step synthesis of ibogaine from pyridine enables access to iboga alkaloids and analogues, with (-)-10-fluoroibogamine showing exceptional psychoplastogenic properties and potent serotonin transporter modulation. |
Abstract
Anecdotal reports and preliminary clinical trials suggest that the psychoactive alkaloid ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, producing long-lasting therapeutic effects across a range of substance use disorders and co-occurring neuropsychiatric diseases such as depression and post-traumatic stress disorder. Here we report a gram-scale, seven-step synthesis of ibogaine from pyridine. Key features of this strategy enabled the synthesis of three additional iboga alkaloids, as well as an enantioselective total synthesis of (+)-ibogaine and the construction of four analogues. Biological testing revealed that the unnatural enantiomer of ibogaine does not produce ibogaine-like effects on cortical neuron growth, while (-)-10-fluoroibogamine exhibits exceptional psychoplastogenic properties and is a potent modulator of the serotonin transporter. This work provides a platform for accessing iboga alkaloids and congeners for further biological study.