Evolution of a compact photoprobe for the dopamine transporter based on (±)-threo-methylphenidate

David J. Lapinsky, Nageswari Yarravarapu, Tammy L. Nolan, Christopher K. Surratt, John R. Lever, Michael Tomlinson, Roxanne A. Vaughan, Howard M. Deutsch

Research output: Contribution to journalArticlepeer-review

Abstract

The development of photoaffinity ligands for determining covalent points of attachment to the dopamine transporter (DAT) has predominantly focused on tropane-based compounds bearing variable-length linkers between the photoreactive group and the inhibitor pharmacophore. To expand the array of photoprobes useful for mapping inhibitor-binding pockets within the DAT, a compact nontropane ligand was synthesized featuring a photoreactive azide and iodine tag directly attached to the aromatic ring of (±)-threo- methylphenidate. (±)-threo-4-Azido-3-iodomethylphenidate [(±)-6; Ki = 4.0 ± 0.8 nM] displayed high affinity for hDAT. Moreover, a radioiodinated analogue of (±)-6 demonstrated covalent ligation to the DAT in cultured cells and rat striatal membranes, thus suggesting the potential utility of this photoprobe in DAT structure-function studies.

Original languageEnglish (US)
Pages (from-to)378-382
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume3
Issue number5
DOIs
StatePublished - May 10 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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