Ibogaine, a derivative of the psychoactive plant, has attracted attention to its anti-adaptive and antidepressant properties. But Ibogaine is a finite resource, extracted from Native Africa plants such as the bush of Iboga (Tabernanthe Iboga) and the voacanga tree of small fruit (African Voacanga). In addition, its use can lead to irregular heartbeat, introducing safety risks and a general need to better understand how its molecular structure leads to its biological effects.
In a study that appears in Nature ChemistryResearchers at the University of California, the Davis Institute for Psychedel and Neurotherapeutics (IPN) report the successful total synthesis of ibogaine, analogues of ibogaine and related pyridine compounds, a relatively economic and widely available chemical.
The strategy of the team allowed the synthesis of four alkaloids related to natural ibain, as well as several unnatural analogues. General yields vary from 6% to 29% after only six or seven steps, a marked increase in the efficiency of previous synthetic efforts to produce similar compounds.
“The complex chemical structure of Ibogaine makes it difficult to produce in significant amounts, and this challenging chemistry has historically limited the efforts of medicinal chemistry to develop improved analogues,” said the corresponding author of the study David E. Olson, director of the IPN and Professor of Chemistry and Biochemistry and Molecular Medicine at UC Davis. “Performing total synthesis solves both problems. We can do it without having to harvest tons and tons of plant material and we can also make analogues, several of which demonstrate really interesting properties.”
Despite the cardiac risk of ibogaine, Olson said that the compound is gaining popularity as a treatment for substance use disorders, traumatic brain injuries and other conditions.
“Some people want to find ways to administer Ibogaine more safely and could mitigate the risk with careful control of cardiac monitoring and magnesium supplements,” he said. “But perhaps we only need Ibogaine 2.0, a better version that still produces these deep anti-adaptive and antidepressant effects, but does not have that heart risk.”
Analogues of interest
Olson highlighted two analogues of interest in Ibogaína from the study.
The first analogue was the image of the Ibogaine mirror. In chemistry, this mirror image trait is known as chirality. Like your left and right hands, such molecular compounds cannot overcome each other.
“Nature only produces a version and if the therapeutic effects of ibogaine come from interactions with another Quiral entity, such as an enzyme or receiver, then you would expect that only the natural version has an effect,” said Olson. “But if it is not specific, both compounds would produce an effect.”
When the researchers tested the effects of ibagaína and its compound of mirror image in neurons, they discovered that only the natural promoted neuronal growth.
“This allowed us to show for the first time that Ibogaine’s effects are probably the result of being linked to a particular receiver,” said Olson. “We do not have all the details of what receiver is, but the anti -swelling compound is a good tool to probe this biology.”
The second analogue of interest was (-)-10-Fluoroibogamin. During the experiments, the compound exhibited exceptional effects on neuronal structure and function, promoting growth and reconnection. In addition, he showed powerful effects on serotonin transporters, which are proteins that regulate serotonin levels in synapses.
“The serotonin transporter is the objective of many antidepressants and is hypothesized that is relevant to the therapeutic efficacy of Ibogaine,” said Olson.
The findings, according to researchers, indicate that (-)-10-Fluoroibogamin should be more thoroughly investigated as a treatment for substance use disorders, depression and related neuropsychiatric diseases.
Safer and more effective medications
According to Olson, the investigation was 10 years in process with the team exploring multiple synthesis routes, each with different levels of effectiveness.
“Many of these analogues of Iboga and analogues of Ibogaine are not made of cheap and easily available starting materials,” said Olson. “The difference with our strategy is that we trust very abundant and economical chemicals, and we can gather the pieces in just a few steps. In general, our goal was to create a more efficient process.”
The research team expects its total synthesis strategy to provide researchers with a roadmap to efficiently access Ibogaine analogues, which finally leads to safer and more effective medicines.
The investigation informed in this publication was supported by the National Institute of General Medical Sciences and National Institute on Drug Abuse of the National Health Institutes under the R35GM182 and R01DA056365 awards numbers. The content is the exclusive responsibility of the authors and does not necessarily represent the official vision of the National Health Institutes. The investigation was also supported by the Camille Dreyfus Master-Scholar award.