Highly potent and selective fluorescent antagonists of the human adenosine A₃ receptor based on the 1,2,4-triazolo[4,3-a]quinoxalin-1-one scaffold

J Med Chem. 2012 Feb 23;55(4):1771-82. doi: 10.1021/jm201722y. Epub 2012 Feb 13.

Abstract

The adenosine-A(3) receptor (A(3)AR) is a G protein-coupled receptor that shows promise as a therapeutic target for cancer, glaucoma, and various autoimmune inflammatory disorders, and as such, there is a need for molecular probes to study this receptor. Here, we report a series of fluorescent ligands containing different linkers and fluorophores based around a 1,2,4-triazolo[4,3-a]quinoxalin-1-one antagonist. One of these conjugates (19) displayed high affinity for the A(3)AR (pK(D) = 9.36 ± 0.12) and is >650-fold selective over other adenosine receptor subtypes. Confocal microscopy revealed clear, displaceable membrane labeling of CHO-A(3) cells with 19, with no detectable labeling of CHO-A(1) cells under identical conditions. This fluorescent ligand was also able to specifically label the A(3)AR in HEK293T cells containing a mixed adenosine receptor population. The subtype specificity, along with its excellent imaging properties, make 19 an ideal tool for studying A(3)AR distribution and organization, particularly in the presence of other adenosine receptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A3 Receptor Antagonists / chemical synthesis*
  • Adenosine A3 Receptor Antagonists / chemistry
  • Adenosine A3 Receptor Antagonists / pharmacology
  • Animals
  • Boron Compounds / chemical synthesis*
  • Boron Compounds / chemistry
  • Boron Compounds / pharmacology
  • CHO Cells
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Fluorescent Dyes / chemical synthesis*
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacology
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Adenosine A3 Receptor Antagonists
  • Boron Compounds
  • Fluorescent Dyes
  • Ligands
  • Quinoxalines
  • Triazoles