Rainforest Tree Synthesizes a Psychotropic Compound

Rainforest Tree Synthesizes a Psychotropic Compound ...

The bark of theGalbulimima belgraveanatree, found only in remote rainforests of Papua New Guinea and northern Australia, has long been used by indigenous people for healing and ceremonial purposes. A tea brewed from the bark is said to relieve pain and fever. Researchers have isolated more than 40 unique substances from the tree bark, but have struggled to reproduce them in the lab or investigate their biology.

Scripps Research scientists have developed a program to synthesize one of these chemicals known as GB18. This program, described in the journalNature, allows them to evaluate its effects on human brain cells and discover that the chemical is linked to several opioid receptors. However, GB18 does not offer a function that might be useful in treating depression or anxiety.

Western medicine hasn''t cornered the market on new therapies, and there are still traditional medicines out there, according to senior authorRyan Shenvi, PhD, a professor of chemistry at Scripps Research. We believe that we may transform GB18 into a useful medicine.

In the 1950s, the plant of Galbulimima belgraveanac, a Melbourne study, began isolating and researching its chemicals, called GB alkaloids. Some of these were found to decrease smooth muscle spasm. Others decreased blood cholesterol. A structural outlier, called GB18, induced mouse behavior and appeared to be psychotropic. However, it was difficult to further pursue their therapeutic potential.

Stone Woo, a graduate of Shenvi, recently researched ways to synthesize other GB alkaloids described inSciencein March 2022. However, it was particularly difficult to place a chemical ring in a hard-to-access pocket, like a mug handle attached to the inside of a cup instead of the outside. Woo discovered a sequence of chemical steps, which similar to the structure of GB18 discovered naturally inGalbulimima belgraveanabark.

Stone was able to create this stunning choreography for assembling small chemicals to construct the complex constellation that is GB18, according to Shenvi. He developed a method to create this ring motif that is unprecedented.

Woo''s method, in turn, allowed him to control which side of GB18 the ring might be tacked on toan innovation with implications for designing variants of GB18 as well as for carrying out other chemical syntheses involving similar rings.

According to Woo, the way we were able to efficiently complete these molecular connections might be beneficial in other situations.

GB18 had been developed for screening experiments conducted by Professor Bryan Roth of UNC Chapel Hill, where they discovered two different opioid receptors in the brain. These receptors had never been identified as targets of any GB alkaloids, thus are the first new receptors linked toGalbulimima belgraveanaactivity in over 35 years.

The researchers are further exploring the potential significance of GB18s binding to the opioid receptors. While opioid medications involved in the ongoing overdose epidemic will activate these receptors, GB18 seems to shut them off. Shenvi believes that GB18 may be used as an antidepressant or anti-anxiety medication, but that it may be more appropriate to human use.

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