title: Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters.
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.
authors: Department of Medicinal Chemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Jacob
authors: J
authors: Andersen
authors: Nicolai
authors: N
authors: Stuhr-Hansen
authors: Linda
authors: L
authors: Zachariassen
authors: Søren
authors: S
authors: Toubro
authors: Stinna M R
authors: SM
authors: Hansen
authors: Jonas N N
authors: JN
authors: Eildal
authors: Andrew D
authors: AD
authors: Bond
authors: Klaus P
authors: KP
authors: Bøgesø
authors: Benny
authors: B
authors: Bang-Andersen
authors: Anders S
authors: AS
authors: Kristensen
authors: Kristian
authors: K
authors: Strømgaard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism*; D001483:Base Sequence; D001572:Benzofurans / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D015283:Citalopram / Q000378:metabolism; D003460:Crystallization; D004252:DNA Mutational Analysis; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011437:Propylamines / Q000378:metabolism; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D001572:Benzofurans; D015283:Citalopram; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493227:SLC6A2 protein, human; C496684:talopram