Discovery of novel purine-based heterocyclic P2X7 receptor antagonists

Bioorg Chem. 2015 Aug:61:58-65. doi: 10.1016/j.bioorg.2015.06.003. Epub 2015 Jun 20.


The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X7 receptor antagonist 5 (IC50 = 13 nM in hP2X7-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 9o exhibited the most potent antagonistic activity, with an IC50 value of 176 ± 37 nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1β release in THP-1 cells stimulated with LPS/IFN-γ/BzATP (IC50 = 120 ± 15 nM). Although 9o was less active than the previous antagonist 5, 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse).

Keywords: Antagonists; Ethidium bromide uptake; Human P2X(7)R; IL-1β; Metabolic stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • HEK293 Cells
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry*
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Purinergic P2X Receptor Antagonists / chemistry*
  • Purinergic P2X Receptor Antagonists / metabolism
  • Purines / chemistry*
  • Receptors, Purinergic P2X7 / chemistry
  • Receptors, Purinergic P2X7 / metabolism
  • Structure-Activity Relationship


  • Heterocyclic Compounds
  • Purinergic P2X Receptor Antagonists
  • Purines
  • Receptors, Purinergic P2X7
  • purine