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<p>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.</p><p></p>

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Efficient and modular synthesis of ibogaine and related alkaloids

  • 期刊论文

  • 发表日期：

    2025年2月6日

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  • 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

摘要

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.