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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Chemical synthesis and biological testing Peer reviewed |
|---|---|
| Topics | Ibogaine |
| Keywords | Natural compound Related alkaloids --10-fluoroibogamine Important compounds Addiction treatment Treating addiction Therapeutic potential Chemical synthesis Efficient gram-scale method New approach Compound creation Compound production Neuropharmacology Brain-healing properties Serotonin modulation Brain chemical |
| Citations | 22 |
| Key points | 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.