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
Summary
Ibogaine, a natural compound, shows promise for treating addiction. Researchers developed an efficient, gram-scale method to create ibogaine and similar compounds from common materials. This new approach allowed for the creation of several related alkaloids and new variations. Notably, one new compound, (-)-10-fluoroibogamine, demonstrated exceptional brain-healing properties and strongly modulated serotonin, a key brain chemical. This breakthrough provides a powerful way to produce these important compounds for exploring their therapeutic potential.
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.