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Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
Peer-reviewed Human StudyObservationalPubMedJournal ArticleMay 16, 2023PMID: 37137306DOI
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.
Authors (21)
LeadDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA.
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA.
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA.
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA.
Department of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: allan.basbaum@ucsf.edu.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA; Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: william.wetsel@duke.edu.
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address: aashish.manglik@ucsf.edu.
Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Suite 508D, San Francisco, CA 94143, USA. Electronic address: bshoichet@gmail.com.
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA. Electronic address: gary.rudnick@yale.edu.