ArticleProceedings of the National Academy of Sciences of the United States of America2011
Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 79 citations in OpenAlex.
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- Novel and emerging anesthetic drugs for the treatments of major depression: a comprehensive review of efficacy, mechanism, and outlook.Frontiers in psychiatry · 2025Review
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- Balancing Therapeutic Efficacy and Safety of MDMA and Novel MDXX Analogues as Novel Treatments for Autism Spectrum Disorder.Psychedelic medicine (New Rochelle, N.Y.) · 2023Review
- Recent Developments in Pharmacotherapy of Depression: Bench to Bedside.Journal of personalized medicine · 2023Review
- Discovery and Development of Monoamine Transporter Ligands.Advances in neurobiology · 2023Review
- The substrate import mechanism of the human serotonin transporter.Biophysical journal · 2022Article
- Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram.RSC medicinal chemistry · 2021Article
- Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.Nature communications · 2021Article
- A non-helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition.The EMBO journal · 2021Article
- Glycine Transporter 2: Mechanism and Allosteric Modulation.Frontiers in molecular biosciences · 2021Review
- Structure Modeling of the Norepinephrine Transporter.Biomolecules · 2020Article
- Toward a Systematic Structural and Functional Annotation of Solute Carriers Transporters-Example of the SLC6 and SLC7 Families.Frontiers in pharmacology · 2020Review
- Structure-Function of the High Affinity Substrate Binding Site (S1) of Human Norepinephrine Transporter.Frontiers in pharmacology · 2020Article
- Structure and Gating Dynamics of NaFrontiers in molecular biosciences · 2019Review
- Clickable photoaffinity ligands for the human serotonin transporter based on the selective serotonin reuptake inhibitor (S)-citalopram.Bioorganic & medicinal chemistry letters · 2018Article
- Structural basis for recognition of diverse antidepressants by the human serotonin transporter.Nature structural & molecular biology · 2018Article
- Structure and Dynamics Study of LeuT Using the Markov State Model and Perturbation Response Scanning Reveals Distinct Ion Induced Conformational States.The journal of physical chemistry. B · 2016Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inhibitors of the serotonin transporter (SERT) and norepinephrine transporter (NET) are widely used in the treatment of major depressive disorder. Although SERT/NET selectivity is a key determinant for the therapeutic properties of these drugs, the molecular determinants defining SERT/NET selectivity are poorly understood. In this study, the structural basis for selectivity of the SERT selective inhibitor citalopram and the structurally closely related NET selective inhibitor talopram is delineated. A systematic structure-activity relationship study allowed identification of the substituents that control activity and selectivity toward SERT and NET and revealed a common pattern showing that SERT and NET have opposite preference for the stereochemical configuration of these inhibitors. Mutational analysis of nonconserved SERT/NET residues within the central substrate binding site was performed to determine the molecular basis for inhibitor selectivity. Changing only five residues in NET to the complementary residues in SERT transferred a SERT-like affinity profile for R- and S-citalopram into NET, showing that the selectivity of these compounds is determined by amino acid differences in the central binding site of the transporters. In contrast, the activity of R- and S-talopram was largely unaffected by any mutations within the central substrate binding site of SERT and NET and in the outer vestibule of NET, suggesting that citalopram and talopram bind to distinct sites on SERT and NET. Together, these findings provide important insight into the molecular basis for SERT/NET selectivity of antidepressants, which can be used to guide rational development of unique transporter inhibitors with fine-tuned transporter selectivity.
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