African psychedelic plants influence the design of antidepressant and anti-addiction candidates

The pharmacology of a traditional African psychedelic herbal medicine called ibogaine has led to the development of two new drug candidates for the potential treatment of addiction and depression. Inspired by ibogaine’s effects on the serotonin transporter (SERT), which is also a serotonin transporter, scientists at the University of California, San Francisco (UCSF), Yale University, and Duke University have virtually screened and discovered 200 million molecular structures. bottom. Blocks SERT in the same way as ibogaine. Their newly reported study showed that at very low doses, two new lead compounds blunt symptoms of both disorders in mice.

“Some people swear by ibogaine to treat addiction, but it’s not a very good drug. It has bad side effects and is not approved for use in the United States,” said Brian Shoichet, Ph. I’m here. “Our compound mimics one of ibogaine’s many pharmacological effects and, at least in mice, reproduces the most desirable effects on behavior,” Shoichet said in a joint paper published by the team. I am the lead author. cell,title”Structure-based discovery of conformation-selective inhibitors of serotonin transportersIn the report, the authors stated, “In behavioral assays in mice, both compounds have anxiolytic- and antidepressant-like activity, up to 200-fold greater potency than fluoxetine (Prozac), One significantly reversed morphine withdrawal symptoms.”

The serotonin transporter (SERT, SLC6A4) is a target of drugs such as antidepressants and psychostimulants, and competitive inhibitors selective for SERT are widely used to treat clinical depression, the authors say. point out. Examples include fluoxetine, citalopram, and paroxetine. Cocaine is a less selective competitive inhibitor of SERT and also blocks closely related transporters of norepinephrine and dopamine (NET and DAT). “In addition, ibogaine and its metabolite noribogaine are alkaloids that inhibit SERT and DAT non-competitively, but with much lower selectivity and affinity for many receptors and channels,” the team continued. I was.

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 century and his 20th century, European and American physicians experimented with the use of this drug in the treatment of various ailments, but the drug did not gain widespread acceptance and eventually many countries was made illegal.

Part of the problem, Shoichet said, is that ibogaine interferes with many aspects of human biology. “Ibogaine binds to hERG, which can cause cardiac arrhythmias, and from a scientific point of view, it’s a ‘dirty’ drug that binds to many targets other than SERT,” Shoichet said.

SERT adopts three conformations: outward-opening, occluded, and inward-opening, the team continued. All known inhibitors, except ibogaine, target the outwardly open state. Unlike his other SERT inhibitors, ibogaine has unusual antidepressant and substance withdrawal effects, stabilizing the open inner structure of SERT. However, the researchers continued, “Ibogaine’s promiscuity and cardiotoxicity limit our understanding of ligands in the inwardly open state.” I didn’t even know how,” Shoichet pointed out.

About their research reported in cell, the researchers used Scheche’s computational docking approach to identify small molecules that interact with the inner open state of SERT. Docking involves systematically testing hypothetical chemical structures for binding with proteins. This allows scientists to identify new drug leads without having to synthesize them in the lab. “We used the low temperature of his SERT complexed with ibogaine in the inwardly open conformation 7 (PDB: 6DZZ) to computationally dock a library of over 200 million make-on-demand molecules. We used an electron microscope structure,” the researchers explained. “From docking with SERT, a diverse set of supercompounds that physically complement SERT’s inwardly open state and are topologically unrelated to previously known inhibitors have been synthesized and biochemically synthesized. It was prioritized for testing.” Population studies to demonstrate the potential real-world utility of the compound include the work of Shoichet, Allan Basbaum, PhD, and Aashish Manglik, MD, PhD (UCSF). Dozens of scientists from around the world were involved. Dr. Gary Rudnick (Yale University). and Dr. Bill Wessel (Duke).

Dr. Shoichet using brain receptor docking to identify therapeutics depression and painRudnick, a SERT expert at Yale University, became interested in SERT and ibogaine after spending a sabbatical in his lab. I wanted to turn it into a better understanding of SERT.

For the Shoichet lab, this was the first docking experiment not with receptors, but with 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 the Basbaum and Wessel team for rigorous testing in animal models of addiction, depression and anxiety. “Suddenly, it burst. At that time, these drugs seemed much more potent than paroxetine. [Paxil]’ said Shoishe. “This compound is also selective for his SERT, meaning mostly against well-known off-targets such as NET, DAT, and serotonergic GPCRs, in contrast to ibogaine’s widespread promiscuity.” There was no activity of any kind,” the team wrote. “All of these compounds represent new chemotypes that are topologically unrelated to known SERT inhibitors in the IUPHAR or ChEMBL databases.”

Manglik, an expert in cryo-electron microscopy (cryo-EM), found that one of two drugs called ‘8090’ fits SERT at the atomic level, in a way very similar to Singh and Shoichet’s computational predictions. Confirmed. These drugs inhibited SERT in a manner similar to ibogaine, but unlike psychedelics, the effects were potent and selective, with ripple effects on a panel of hundreds of other receptors and transporters. There was no The authors concluded, “In behavioral assays in mice, both compounds have anxiolytic- and antidepressant-like activity, up to 200-fold more potent than fluoxetine (Prozac), and one is more potent than morphine.” It significantly reversed my withdrawal symptoms.”

“This is exactly how science should be done,” Basbaum said. “We recruited a group of people with different areas of expertise to come up with something that could really make a difference … that this kind of potency gives us a better treatment window with no side effects. Reducing the dose by almost 200-fold could make a big difference for patients, and, as the authors noted, “the effects observed against other flexible targets As such, new chemotypes confer novel in vitro activities, which likely contributed to the unusually high potency of new SERT inhibitors in animal models of depression-like responses…The selectivity of novel SERT inhibitors and NET , DATs, off-targets such as serotonergic GPCRs, and inhibitors of specific SERT conformational states could be useful as tool molecules to probe transporter function and therapeutic translation.”

“This kind of project starts by visualizing what kind of molecules fit into the protein, docking the library, optimizing it, and relying on the team to show that the molecule works,” he said. , a paper in which he worked as a postdoc in Scheuse’s lab. “Today, we know there is a lot of untapped potential for therapies that target SERT.”

Shoichet submitted the structures of both new molecules to Sigma Aldrich with the goal of allowing other scientists to test them further while continuing to search for more precise molecules. “…we are making them publicly available through our Millipore-Sigma probe collection,” the researchers say in their paper. New prospective treatments are needed as millions of patients continue to suffer from depression and addiction.