Inspired by a traditional African psychedelic herbal medicine called ibogaine, scientists have identified two new drug candidates that could treat addiction and depression in mice by targeting the serotonin transporter. developed. These compounds mimic the desired effects of ibogaine without the side effects and further trials are underway to explore their therapeutic potential.
Targeting molecules are more potent than SSRI antidepressants and avoid ibogaine’s dangerous side effects.
Harnessing the medicinal properties of a traditional African psychedelic plant called ibogaine, scientists have created two new drugs that may be used to treat addiction and depression. Administration of these compounds at very low doses was able to alleviate symptoms associated with both diseases in mice.
This study was recently published in the journal cellis based on studies of how ibogaine interacts with the serotonin transporter (SERT), a common target of SSRI antidepressants such as fluoxetine (Prozac). A joint research team from UCSF, Yale University, and Duke University virtually screened 200 million molecular structures to identify those that interact with SERT in a manner similar to ibogaine.
“Some people swear by using ibogaine to treat addiction, but it’s not a very good drug. Professor Brian Shoichett, Ph.D. “Our compound mimics one of ibogaine’s many pharmacological effects, yet still reproduces its most desirable effects on behavior, at least in mice.”
Shoichet, Allan Basbaum, PhD, and dozens of scientists from the lab of Aashish Manglik, MD, PhD (UCSF). Dr. Gary Rudnick (Yale University); and his Dr. Bill Wetsel (Duke) contributed to demonstrating the real-world promise of these novel molecules, initially identified using his Shoichet’s computational docking method. Did.
Docking involves systematically testing virtual chemical structures for binding to proteins, allowing scientists to identify new drug leads without synthesizing them in the lab.
“This kind of project starts by visualizing what kinds of molecules fit into the protein, then docks the library, optimizes it, and then relies on the team to show that the molecule works. said co-first investigator Dr. Isha Singh. The author of this paper worked as a postdoctoral fellow in the Shoichett lab. “We know there is a lot of untapped potential for therapies that target SERT.”
Ibogaine is found in the root of the iboga plant, which is native to Central Africa and has been used in shamanic rituals for thousands of years. During the 19th and 20th centuries, European and American physicians experimented with the use of this drug to treat various ailments, but the drug did not gain widespread acceptance and eventually became illegal in many countries. I was.
Part of the problem, Scheutche explained, is that ibogaine interferes with many aspects of human biology.
“Ibogaine binds to hERG, which can cause cardiac arrhythmias. From a scientific point of view, ibogaine is a ‘dirty’ drug that binds to many targets other than SERT,” said Schaeuche. “Until we did this experiment, we didn’t even know if ibogaine’s benefits came from binding to SERT.”
Dr. Shoichett, who has used docking to brain receptors to identify drugs to treat depression and pain, became interested in SERT and ibogaine after Yale University SERT expert Rudnick spent a sabbatical in his lab. now have Singh said he picked up the project in 2018, hoping to connect the topic of ibogaine to his deeper understanding of SERT.
This was the first docking experiment for the Shoichet lab, not on receptors but on transporters (proteins that move molecules in and out of cells). A single docking reduced the virtual library from 200 million to just 49 molecules, 36 of which could be synthesized. Rudnick’s lab tested them and found that 13 inhibited her SERT.
The team then held a virtual reality-guided “docking party” to help Singh prioritize five molecules for optimization. His two most potent SERT inhibitors were shared with Basbaum and Wessel’s team for rigorous testing in animal models of addiction, depression and anxiety.
“Suddenly, those drugs burst. At that time, they seemed to be much more powerful than paroxetine.” [Paxil]’ said Scheutche.
Manglik, an expert in cryo-electron microscopy (cryo-EM), said one of the two drugs, called 8090, could induce SERT at the atomic level, much like the computational predictions of Singh and Shoichet. was confirmed to be compatible with These drugs inhibited SERT in a manner similar to that of ibogaine, but unlike psychedelics, their effects were potent and selective, with no knock-on effect on a panel of hundreds of other receptors and transporters. I didn’t.
“With this kind of efficacy, we hope to have a better duration of treatment without side effects,” Basbaum said. “Reducing the dose by almost 200-fold can make a big difference for patients.
Shoichet has submitted the structures of both new molecules to chemical manufacturer Sigma-Aldrich, with the goal of making them available for further testing by other scientists while continuing to search for more precise molecules. bottom.
As millions of patients continue to suffer from depression and addiction, new and prospective treatments are needed.
“This is the true way science should be done,” Busbaum said. “We brought together a group of people with different areas of expertise to come up with something that could really make a difference.”
Reference: “Structure-based discovery of structure-selective inhibitors of serotonin transporters” Isha Singh, Anubha Seth, Christian B. Billesbølle, Joao Braz, Ramona M. Rodriguiz, Kasturi Roy, Bethlehem Bekele, Veronica Craik, Xi-Ping Huang, Danila Boitsov, Vladimir M. Pogorelov, Parnian Luck, Henry O’Donnell, Walter Sandtner, John J. Irwin, Brian L. Ross, Alan I. Basbaum, William C. Wessel, Arshish・Manglik, Brian K. Shoichett, Gary Rudnick, May 2, 2023 cell.
DOI: 10.1016/j.cell.2023.04.010
This research was conducted with the Defense Advanced Research Projects Agency. National Institutes of Health.
