title: The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors.
abstract: The interaction of the S- and R-enantiomers (escitalopram and R-citalopram) of citalopram, with high- and low-affinity binding sites in COS-1 cell membranes expressing human SERT (hSERT) were investigated. Escitalopram affinity for hSERT and its 5-HT uptake inhibitory potency was in the nanomolar range and approximately 40-fold more potent than R-citalopram. Escitalopram considerably stabilised the [3H]-escitalopram/SERT complex via an allosteric effect at a low-affinity binding site. The stereoselectivity between escitalopram and R-citalopram was approximately 3:1 for the [3H]-escitalopram/hSERT complex. The combined effect of escitalopram and R-citalopram was additive. Paroxetine and sertraline mainly stabilised the [3H]-paroxetine/hSERT complex. Fluoxetine, duloxetine and venlafaxine have only minor effects. 5-HT stabilised the [125I]-RTI-55, [3H]-MADAM, [3H]-paroxetine, [3H]-fluoxetine and [3H]-venlafaxine/SERT complex to some extent. Thus, escitalopram shows a unique interaction with the hSERT compared with other 5-HT reuptake inhibitors (SSRIs) and, in addition to its 5-HT reuptake inhibitory properties, displays a pronounced effect via an affinity-modulating allosteric site.
authors.affiliation: Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital of Aarhus University, Skovagervej 2, DK-8240 Risskov, Denmark.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Chen
authors.forename: Mads Breum
authors.initials: MB
authors.lastname: Larsen
authors.forename: Connie
authors.initials: C
authors.lastname: Sánchez
authors.forename: Ove
authors.initials: O
authors.lastname: Wiborg
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015283:Citalopram / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D015283:Citalopram; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human