Ibogaine — a psychoactive plant derivative — has attracted attention for its anti-addictive and anti-depressant properties. But ibogaine is a finite resource, extracted from plants native to Africa like the iboga shrub (Tabernanthe iboga) and the small-fruited voacanga tree (Voacanga africana). Further, its use can lead to irregular heartbeats, introducing safety risks and an overall need to better understand how its molecular structure leads to its biological effects.
In a study appearing in , researchers at the Ƶ, Davis (IPN) report the successful total synthesis of ibogaine, ibogaine analogues and related compounds from pyridine — a relatively inexpensive and widely available chemical.
The team’s strategy enabled the synthesis of four naturally occurring ibogaine-related alkaloids as well as several non-natural analogues. Overall yields ranged from 6% to 29% after only six or seven steps, a marked increase in efficiency from previous synthetic efforts to produce similar compounds.
“Ibogaine’s complex chemical structure makes it hard to produce in significant quantities, and this challenging chemistry has historically limited medicinal chemistry efforts to develop improved analogues,” said the study’s corresponding author David E. Olson, director of the IPN and a professor of chemistry and biochemistry and molecular medicine at UC Davis. “Performing total synthesis solves both problems. We can make it without having to harvest tons and tons of plant material and we can also make analogues, several of which are demonstrating really interesting properties.”
Despite the cardiac risk of ibogaine, Olson noted that the compound is gaining popularity as a treatment for substance use disorders, traumatic brain injury and other conditions.
“Some people want to find ways to administer ibogaine more safely and you might be able to mitigate risk with careful cardiac monitoring and magnesium supplementation,” he said. “But maybe we just need ibogaine 2.0, a better version that still produces these profound anti-addictive and anti-depressent effects but doesn’t have that cardiac risk.”
Analogues of interest
Olson highlighted two ibogaine analogues of interest from the study.
The first analogue was the mirror image of ibogaine. In chemistry, this mirror image trait is referred to as chirality. Like your left and right hands, such molecular compounds can’t be superposed on each other.
“Nature only produces one version and if the therapeutic effects of ibogaine are coming from interactions with another chiral entity, like an enzyme or receptor, then you would expect only the natural version to have an effect,” Olson said. “But if it’s non-specific, then both compounds would produce an effect.”
When the researchers tested the effects of ibogaine and its mirror image compound on neurons, they discovered that only the natural one promoted neuronal growth.
“This allowed us to show for the first time that ibogaine’s effects are probably the result of it being bound to a particular receptor,” Olson said. “We don’t have all the details of what receptor that is, but the unnatural