Scientists have discovered two new potential drugs for the treatment of addiction and depression, inspired by a traditional African psychedelic plant medicine called ibogaine. These drugs target the serotonin transporter and have shown promising effects in mice, mimicking ibogaine’s positive effects without its harmful side effects. Further research is being conducted to explore their therapeutic potential.
The newly developed drug candidates are more potent than SSRIs, a commonly used type of antidepressant, and they avoid the dangerous side effects associated with ibogaine.
The study, recently published in the journal Cell, focused on the interaction between ibogaine and the serotonin transporter (SERT). A collaborative research team from UCSF, Yale, and Duke universities screened millions of molecular structures virtually to identify compounds that interacted with SERT in a similar manner to ibogaine.
According to Brian Shoichet, a professor at the UCSF School of Pharmacy and co-senior author of the study, ibogaine is not an ideal drug due to its side effects and lack of approval in the United States. The newly developed compounds replicate some of ibogaine’s pharmacological effects, particularly in behavior, at least in mice.
Researchers from various universities, including UCSF, Yale, and Duke, collaborated to demonstrate the potential of these novel molecules. The compounds were initially identified using computational docking methods developed by Brian Shoichet. Docking involves testing virtual chemical structures for their ability to bind with a protein, eliminating the need for synthesis in the laboratory.
The medicinal properties of ibogaine, found in the roots of the iboga plant native to central Africa, have been utilized in shamanistic rituals for centuries. However, its use as a treatment in Europe and the U.S. faced challenges due to its interference with various biological processes.
The study revealed that ibogaine’s benefits may stem from its interaction with SERT, a finding that sparked the interest of Brian Shoichet, who had previously used docking methods to identify drugs for depression and pain. The project focused on SERT as a transporter protein instead of a receptor, resulting in the identification of 49 synthesizable molecules, with 13 of them inhibiting SERT.
Two of the most potent SERT inhibitors were selected for further optimization and rigorous testing on animal models of addiction, depression, and anxiety. The drugs showed potent and selective effects on SERT, similar to ibogaine, but without impacting other receptors and transporters.
The researchers, including Aashish Manglik, an expert in cryo-electron microscopy, confirmed that one of the drugs, named ‘8090, fit into SERT at the atomic level, as predicted by computational models. The effectiveness of the drugs and their potential for reducing side effects were considered significant advancements for patient treatment.
The structures of the two new molecules have been submitted to Sigma Aldrich, a chemical manufacturing company, to facilitate further testing by other scientists. Meanwhile, Brian Shoichet continues to search for more precise molecules.
Given the prevalence of depression and addiction among millions of patients, the discovery of these potential therapies represents a significant scientific breakthrough. The study was funded by the Defense Advanced Research Projects Agency and the National Institutes of Health.
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Frequently Asked Questions (FAQs) about drug candidates
What inspired the development of these new drug candidates?
The development of these new drug candidates was inspired by a traditional African psychedelic plant medicine called ibogaine, known for its potential in treating addiction and depression.
How do these drug candidates differ from traditional antidepressants (SSRIs)?
These drug candidates are reported to be more powerful than SSRIs (selective serotonin reuptake inhibitors), a commonly used type of antidepressant. They also aim to avoid the dangerous side effects associated with ibogaine.
What is the therapeutic potential of these drug candidates?
The drug candidates have shown promising effects in targeting the serotonin transporter and treating addiction and depression in mice. Further testing is underway to explore their therapeutic potential in humans.
What were the challenges with using ibogaine as a drug?
Ibogaine, despite being recognized for its potential benefits, has several limitations. It interferes with various aspects of human biology, binds to multiple targets beyond the serotonin transporter (SERT), and can cause heart arrhythmias. Additionally, it is not approved for use in the United States.
How were these drug candidates identified and tested?
The drug candidates were identified through virtual screening of molecular structures that interacted with SERT similarly to ibogaine. Computational docking methods were utilized to narrow down the potential compounds. Rigorous testing on animal models of addiction, depression, and anxiety was conducted to evaluate their efficacy and selectivity.
Are these drug candidates ready for human use?
While these drug candidates have shown promise in preclinical studies, further research is needed before they can be considered for human use. The compounds have been submitted for testing by other scientists, and ongoing efforts are focused on finding more precise molecules for therapeutic purposes.
More about drug candidates
- Cell: Structure-based discovery of conformationally selective inhibitors of the serotonin transporter
- UCSF: Scientists Develop Two New Drug Candidates That Could Treat Addiction and Depression
- Yale News: Scientists develop two new drug candidates that could treat addiction and depression
- Duke Today: Scientists Develop Two New Drug Candidates That Could Treat Addiction and Depression
