Scripps Research scientists report that they have developed a method to synthesize one of the chemicals found in the Galbulimima belgraveana tree, found only in remote rainforests of Papua New Guinea and northern Australia and long used by indigenous people for both healing and ceremony. A tea brewed from the bark not only induces a dreamlike state but is said to ease pain and fever.

To probe these effects, researchers have isolated more than 40 unique chemicals from the tree bark but have struggled to reproduce the compounds in the lab or study their biology. The Scripps team, which published its study “Synthesis and target annotation of the alkaloid GB18” in Nature, includes a new type of reaction that could be useful in synthesizing other chemicals. It also let them produce enough of one of the tree bark’s compounds, GB18, to study its effects on human brain cells.

The scientists discovered that the chemical binds to opioid receptors—the same molecules targeted by many painkillers. While opioid painkillers activate these receptors, however, GB18 turns them off, a function that some researchers hypothesize could be useful in treating depression and anxiety.

“This goes to show that Western medicine hasn’t cornered the market on new therapeutics; there are traditional medicines out there still waiting to be studied,” says senior author Ryan Shenvi, PhD, a professor of chemistry at Scripps Research. “Our hope is that we can turn GB18 into a useful medicine.”

“Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans. Limited, variable supply of GB alkaloids, however, has impeded their biological exploration and clinical development,” write the investigators.

“Here we report a solution to the supply of GB18, a structural outlier and putative psychotropic principle of Galbulimima bark. Efficient access to its challenging tetrahedral attached-ring motif required the development of a ligand-controlled endo-selective cross-electrophile coupling and a diastereoselective hydrogenation of a rotationally-dynamic pyridine.

“Reliable, gram-scale access to GB18 allowed its assignment as a potent antagonist of kappa- and mu- opioid receptors—the first new targets in 35 years—and lay the foundation to navigate and understand the biological activity of Galbulimima metabolites.”

Morphine binding to opioid receptors, illustration
Morphine binding to opioid receptor. Computer illustration of morphine molecules (orange) binding to mu-opioid receptors (grey) in a cell membrane (purple and yellow). Opioid receptors are found on nerve cells. When pain is detected by the body, endorphins are released and attach to the receptors, starting a reaction that modulate pain perception. Opioid drugs such as morphine mimic endorphins. [Juan Gaertner/Science Photo Library/Getty Images]

In the 1950s, G. belgraveana caught the attention of Australian researchers, who began isolating and studying its chemicals (GB alkaloids), a number of which were found to decrease smooth muscle spasm. Some increased heart rate, whereas others decreased it. A structural outlier, GB18, affected mouse behavior and appeared to be psychotropic. But without the ability to recreate the compounds in the lab, it was difficult to further pursue their potential therapeutic value.

While some members of the Shenvi lab recently worked out ways to synthesize other GB alkaloids, described in an article in Science in March, Scripps graduate student Stone Woo tackled GB18. Its structure was particularly tricky, with a chemical ring tucked in a hard-to-access pocket, like a mug handle attached to the inside of a cup instead of the outside.

Woo discovered a series of chemical steps, however, that could produce the desired structure, exactly mimicking the structure of GB18 found naturally in G. belgraveana bark.

“Stone was able to devise this beautiful choreography for bringing together small chemicals to assemble the complex constellation that is GB18,” explains Shenvi. “He developed a way to build this ring motif that is unprecedented.”

The method that Woo devised, in fact, let him control which side of GB18 the ring could be tacked on to—an innovation with implications for creating variants of GB18 as well as for carrying out other chemical syntheses involving similar rings.

“The way we were able to efficiently assemble these molecular connections could prove useful in other contexts,” says Woo.

Once the researchers had a means to synthesize GB18, they produced enough of it to use in screening experiments conducted through the National Institute of Mental Health Psychoactive Drug Screening Program. These screens revealed that GB18 bound to two different opioid receptors in the brain. These receptors had never before been identified as targets of any GB alkaloids and represent the first new receptors linked to G. belgraveana activity in more than 35 years.

Now, the researchers are further studying the exact biological impact of GB18’s binding to the opioid receptors. While opioid drugs involved in the ongoing overdose epidemic will activate these receptors, GB18 seems to shut them off. Shenvi says that may make GB18 useful as an antidepressant or anti-anxiety drug, but more work is needed to adapt it to human use.

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