High ligand efficiency quinazoline compounds as novel A2A adenosine receptor antagonists

Eur J Med Chem. 2022 Nov 5:241:114620. doi: 10.1016/j.ejmech.2022.114620. Epub 2022 Jul 22.


The past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A2A receptor (A2AAR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A2AAR antagonists with high ligand efficiency. This class of molecules has been discovered by a virtual screening and bears no structural semblance with reference antagonist ZM-241385. More precisely, we identified a series of 2-aminoquinazoline as promising A2AAR antagonists. Among them, one compound showed a high affinity towards A2AAR (21a, Ki = 20 nM). We crystallized this ligand in complex with A2AAR, confirming one of our predicted docking poses and opening up possibilities for further optimization to derive selective ligands for specific adenosine receptor subtypes.

Keywords: A(2A) adenosine Receptor; Alzheimer; Crystallography; Parkinson; Quinazoline.

MeSH terms

  • Adenosine A2 Receptor Antagonists* / chemistry
  • Adenosine A2 Receptor Antagonists* / pharmacology
  • Ligands
  • Molecular Docking Simulation
  • Purinergic P1 Receptor Antagonists* / pharmacology
  • Quinazolines / pharmacology
  • Receptor, Adenosine A2A / chemistry
  • Structure-Activity Relationship


  • Adenosine A2 Receptor Antagonists
  • Ligands
  • Purinergic P1 Receptor Antagonists
  • Quinazolines
  • Receptor, Adenosine A2A