Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
Isha Singh, Anubha Seth, Christian B. Billesbølle, Joao M 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, Gary Rudnick
Cell May 11, 2023 DOI: 10.1016/j.cell.2023.04.010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Computational docking and experimental validation Peer reviewed |
|---|---|
| Population | Mice |
| Topics | Addiction Depression Serotonin |
| Keywords | Docking Functional selectivity Serotonin transporter Potent compounds Promising path Screened molecules Pharmacology anti-depressant effects Anti-anxiety effects Reversing morphine withdrawal Improved safety Neuroscience anti-depressant Screened ultra-large libraries |
| Citations | 97 |
| Key findings | Two potent, low-nanomolar SERT inhibitors that stabilize an outward-closed state showed anxiolytic- and anti-depressant-like activity up to 200-fold better than fluoxetine in mice, and one reversed morphine withdrawal effects. |
Abstract
The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 4
- Efficient and modular synthesis of ibogaine and related alkaloids. Nature Chemistry March 1, 2025
- Applications and Potential of In Silico Approaches for Psychedelic Chemistry Molecules August 9, 2023
- Deciphering Ibogaine’s Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses Journal of the American Chemical Society December 26, 2025
- Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine National Science Review September 5, 2025
Cites 11
- The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proceedings of the National Academy of Sciences March 1, 1992
- Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature May 1, 2019
- Treatment of acute opioid withdrawal with ibogaine. American Journal on Addictions 1999
- Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. Journal of Biological Chemistry October 5, 2007
- The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. Journal of Biological Chemistry May 25, 2012
and 6 more in the library