Binding-induced fluorescence of serotonin transporter ligands: A spectroscopic and structural study of 4-(4-(Dimethylamino)phenyl)-1- methylpyridinium (APP+) and APP+ analogues

James N. Wilson, Lucy Kate Ladefoged, W. Michael Babinchak, Birgit Schiøtt

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The binding-induced fluorescence of 4-(4-(dimethylamino)-phenyl)-1- methylpyridinium (APP+) and two new serotonin transporter (SERT)-binding fluorescent analogues, 1-butyl-4-[4-(1-dimethylamino)phenyl]- pyridinium bromide (BPP+) and 1-methyl-4-[4-(1-piperidinyl)phenyl]- pyridinium (PPP+), has been investigated. Optical spectroscopy reveals that these probes are highly sensitive to their chemical microenvironment, responding to variations in polarity with changes in transition energies and responding to changes in viscosity or rotational freedom with emission enhancements. Molecular docking calculations reveal that the probes are able to access the nonpolar and conformationally restrictive binding pocket of SERT. As a result, the probes exhibit previously not identified binding-induced turn-on emission that is spectroscopically distinct from dyes that have accumulated intracellularly. Thus, binding and transport dynamics of SERT ligands can be resolved both spatially and spectroscopically.

Original languageEnglish (US)
Pages (from-to)296-304
Number of pages9
JournalACS Chemical Neuroscience
Volume5
Issue number4
DOIs
StatePublished - Apr 16 2014

Keywords

  • fluorescence
  • induced fit docking
  • LeuT
  • quantum polarized ligand docking
  • Serotonin
  • SERT

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

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