From a rainforest tree, chemists create a psychoactive chemical

Credit: The Scripps Research Institute

Papua New Guinea and northern Australia’s Galbulimima belgraveana tree bark has long been used by indigenous people for both therapeutic and ritual purposes. Brewing bark tea is supposed to help alleviate pain and fever as well as generate a trance-like mood. Researchers have isolated more than 40 distinct chemicals from the bark of the tree, but they have been unable to replicate the compounds in the lab or analyse their biology in order to investigate these effects.

One of these compounds, known as GB18, has now been synthesised by Scripps Research scientists. Nature published an online article on May 12, 2022, detailing a novel sort of chemical reaction that could be used to synthesise additional substances. They were able to make enough GB18 this way to analyse the chemical’s effects on human brain cells and discover that it attaches to opioid receptors, the same molecules that many medicines target. In contrast to opioid medications, GB18 inhibits the activation of these receptors—a property that some researchers believe may be effective in the treatment of depression and anxiety disorders.

Researchers at Scripps Research said the findings “go to illustrate that Western medicine hasn’t cornered the market on new treatments; there are traditional medicines out there still waiting to be researched.” “It is our goal that GB18 can be used as a therapeutic agent.”

In the 1950s, Australian researchers began identifying and analysing Galbulimima belgraveana’s compounds, known as GB alkaloids. Some GB alkaloids have been shown to reduce muscular spasm. Some people’s heart rates went up, while others went down. GB18, a structural outlier, had an effect on the behaviour of mice and appeared to have psychoactive properties. However, further exploration of the compounds’ medicinal potential was hampered by their inability to be synthesised in the laboratory.

Stone Woo, a graduate student in the Scripps Institution of Oceanography’s (SIO) Stone Woo Research Group, was the first to synthesise GB18. With a chemical ring tucked away in a hard to access location, like a cup handle attached to the interior of a cup instead of the exterior, its structure proved particularly challenging. The structure of GB18, which may be found in the bark of Galbulimima belgraveana, was discovered by Woo through a series of chemical procedures.

GB18, the intricate constellation built by Stone, was made possible by the choreography the scientist devised for bringing together tiny compounds. It’s the first time anyone has come up with a means to make this ring pattern like this.”

For the first time ever, Woo’s method allowed him to choose attach rings to either one or the other side of GB18—a breakthrough that could lead to new GB18 variants and other chemical syntheses that utilise comparable rings in the future.

It’s possible that Woo’s method of quickly assembling molecular connections will be valuable in other circumstances.

The National Institute of Mental Health Psychoactive Drug Screening Program, which is directed by Professor Bryan Roth of the University of North Carolina in Chapel Hill, was able to employ GB18 in screening trials after the researchers acquired a way to synthesis it. GB18 was found to bind to two distinct opioid receptors in the brain, according to these tests. They are the first receptors associated with Galbulimima belgraveana action in over 35 years and have never before been identified as targets of any GB alkaloids.

Further research is being done to determine exactly how the binding of GB18 to opioid receptors impacts the body. GB18 appears to be able to prevent opioids from interacting with these receptors, which have been implicated in the opioid overdose crisis. While it may be effective as an antidepressant or anti-anxiety medicine, Shenvi thinks that further research is needed before it can be used in humans.

Further information: Stone Woo et al, Synthesis and target annotation of the alkaloid GB18, Nature (2022). DOI: 10.1038/s41586-022-04840-9

Journal information: Science , Nature

Source: The Scripps Research Institute