2. Academic Validation
  3. High ligand efficiency quinazoline compounds as novel A2A adenosine receptor antagonists

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.
Raphaël Bolteau 1,  Romain Duroux 1,  Amélie Laversin 1,  Brandon Vreulz 1,  Anna Shiriaeva 2,  Benjamin Stauch 3,  Gye Won Han 3,  Vadim Cherezov 3,  Nicolas Renault 4,  Amélie Barczyk 4,  Séverine Ravez 1,  Mathilde Coevoet 1,  Patricia Melnyk 1,  Maxime Liberelle 5,  Saïd Yous 1
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France.
  • 2 Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • 3 Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern Califorinia, Los Angeles, CA, USA; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • 4 Univ. Lille, Inserm, U995 - LIRIC - Lille Inflammation Research International Center, ICPAL, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France.
  • 5 Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France. Electronic address: [email protected].
PMID: 35933788 DOI: 10.1016/j.ejmech.2022.114620
Abstract

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.

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