More potent than SSRIs Scientists develop two new drug candidates that could treat addiction and depression

The targeted molecules are more potent than SSRI antidepressants and avoid the dangerous side effects of ibogaine.

Scientists have created two potential new drugs for the treatment of addiction and depression by drawing on the medicinal properties of a traditional African psychedelic plant called ibogaine. When administered at extremely low doses, these compounds were able to alleviate symptoms associated with both ailments in mice.

The study, which was recently published in the journal Cell, based his research on how ibogaine interacts with the serotonin transporter (SERT), a common target for SSRI antidepressants such as fluoxetine (Prozac). A collaborative research team from UCSF, Yale and Duke universities examined virtually 200 million molecular structures to identify those that interacted with SERT in a similar way to ibogaine.

 

Some people swear by ibogaine for addiction treatment, but it’s not a very good drug. It has adverse side effects and is not approved for use in the United States, said Brian Shoichet, Ph.D., co-senior author and professor in the UCSF School of Pharmacy. Our compounds mimic just one of ibogaine’s many pharmacological effects and yet replicate its more desirable behavioral effects, at least in mice.

Dozens of scientists from the laboratories of Shoichet, Allan Basbaum, PhD, and Aashish Manglik, MD, PhD, (UCSF); Gary Rudnick, PhD, (Yale); and Bill Wetsel, PhD, (Duke) helped demonstrate the real-world promise of these new molecules, which were initially identified using Shoichet’s computational docking methods.

Docking involves systematically testing virtual chemical structures for binding to a protein, allowing scientists to identify new drug leads without having to synthesize them in the lab.

 

This type of project starts with visualizing what types of molecules will fit a protein, docking the library, optimizing, and then relying on a team to show how the molecules work, said Isha Singh, Ph.D., co- first author of the journal who did the work as a postdoc in Shoichets’ lab. We now know that there is a lot of untapped therapeutic potential in targeting the SERT.

Ibogaine is found in the roots of the iboga plant, native to central Africa, and has been used for millennia in shamanic rituals. In the 19th and 20th centuries, physicians in Europe and the United States experimented with its use in treating a variety of ailments, but the drug never gained widespread acceptance and was eventually made illegal in many villages.

Part of the problem, Shoichet explained, is that ibogaine interferes with many aspects of human biology.

Ibogaine binds to hERG, which can cause cardiac arrhythmias, and from a scientific standpoint, it’s a dirty drug, binding to many targets beyond SERT, Shoichet said. Prior to this experiment, we didn’t even know if ibogaine’s benefits came from its connection to SERT.

 

Shoichet, who has used docking on brain receptors to identify drugs to treat depression and pain, became interested in SERT and ibogaine after Rudnick, a SERT expert at Yale, took a gap year in his laboratory. Singh picked up the project in 2018, hoping to turn the buzz around ibogaine into a better understanding of SERT.

It was the Shoichet labs’ first docking experiment on a transporter protein that moves molecules in and out of cells rather than a receptor. One docking cycle reduced the virtual library from 200 million to just 49 molecules, 36 of which could be synthesized. Rudnicks’ lab tested these and found that 13 inhibited SERT.

The team then held VR-guided docking parties, to help Singh prioritize five molecules for optimization. The two most potent SERT inhibitors were shared with the Basbaum and Wetsels teams for rigorous testing in animal models of addiction, depression and anxiety.

Suddenly, they erupted when these drugs seemed so much more powerful than even paroxetine [Paxil]Shoichet said.

 

Manglik, an expert in cryo-electron microscopy (cryo-EM), confirmed that one of the two drugs, dubbed 8090, fit SERT at the atomic level in a way that closely resembled the computational predictions of Singh and Shoichet. The drugs inhibited SERT in a similar way to ibogaine, but unlike the psychedelic, their effect was potent and selective, with no spillover effects on a panel of hundreds of other receptors and transporters.

With this kind of potency, we hope to have a better therapeutic window without side effects, Basbaum said. Dropping the dose nearly 200-fold could make a big difference for patients.

Shoichet presented the structures of both new molecules to Sigma Aldrich, the chemical manufacturing company, with the aim of making them available for further testing by other scientists, as he continues to search for more precise molecules

With millions of patients continuing to suffer from depression or addiction, new prospective therapies are needed.

 

This is really the way science should be done, Basbaum said. We took on a group with experience in disparate fields and found something that could really make a difference.

Reference: Structure-Based Discovery of Conformationally Selective Serotonin Transporter Inhibitors by Isha Singh, Anubha Seth, Christian B. Billesblle, Joao Braz, Ramona M. Rodriguiz, Kasturi Roy, Bethlehem Bekele, Veronica Craik, Xi-Ping Huang, Danila Boytsov , Vladimir M. Pogorelov, Parnian Lak, Henry O’Donnell, Walter Sandtner, John J. Irwin, Bryan L. Roth, Allan I. Basbaum, William C. Wetsel, Aashish Manglik, Brian K. Shoichet, and Gary Rudnick, May 2 2023, Cell.
DOI: 10.1016/j.cell.2023.04.010

The study was funded by the Defense Advanced Research Projects Agency and the National Institute of Health.