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

Eur Neuropsychopharmacol. 2005 Mar;15(2):193-8. doi: 10.1016/j.euroneuro.2004.08.008.

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.

Publication types

  • Comparative Study

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Citalopram / metabolism*
  • Citalopram / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Modulators*
  • Membrane Transport Proteins / antagonists & inhibitors*
  • Membrane Transport Proteins / metabolism*
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors / metabolism*
  • Serotonin Uptake Inhibitors / pharmacology
  • Stereoisomerism

Substances

  • Membrane Glycoproteins
  • Membrane Transport Modulators
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Citalopram