Characterization of a selective and potent antagonist of human P2X(7) receptors, AZ11645373

Br J Pharmacol. 2006 Dec;149(7):880-7. doi: 10.1038/sj.bjp.0706933. Epub 2006 Oct 9.


Background and purpose: The ATP-gated P2X(7) receptor has been shown to play a role in several inflammatory processes, making it an attractive target for anti-inflammatory drug discovery. We have recently identified a novel set of cyclic imide compounds that inhibited P2X(7) receptor-mediated dye uptake in human macrophage THP-1 cells. In this study the actions and selectivity of one of these compounds, AZ11645373, were characterized.

Experimental approach: We measured membrane currents, calcium influx, and YOPRO-1 uptake from HEK cells expressing individual P2X receptors, and YOPRO1 uptake and interleukin-1beta release from THP-1 cells in response to ATP and the ATP analogue benzoylbenzoyl ATP (BzATP).

Key results: AZ11645373 up to 10 microM, had no agonist or antagonist actions on membrane currents due to P2X receptor activation at human P2X(1), rat P2X(2), human P2X(3), rat P2X(2/3), human P2X(4), or human P2X(5) receptors expressed in HEK cells. AZ11645373 inhibited human P2X(7) receptor responses in HEK cells in a non-surmountable manner with K (B) values ranging from 5 - 20 nM, with mean values not significantly different between assays. K (B) values were not altered by removing extracellular calcium and magnesium. ATP-evoked IL-1beta release from lipopolysaccharide-activated THP-1 cells was inhibited by AZ11645373, IC(50) = 90 nM. AZ11645373 was > 500-fold less effective at inhibiting rat P2X(7) receptor-mediated currents with less than 50% inhibition occurring at 10 microM.

Conclusions and implications: AZ11645373 is a highly selective and potent antagonist at human but not rat P2X(7) receptors and will have much practical value in studies of human cells.

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / pharmacology
  • Aniline Compounds
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Benzoxazoles
  • Calcium Signaling / drug effects
  • Cell Line
  • Dose-Response Relationship, Drug
  • Fluorescent Dyes
  • Humans
  • Imides / pharmacology*
  • Interleukin-1beta / metabolism
  • Ion Channel Gating / drug effects
  • Lipopolysaccharides / pharmacology
  • Membrane Potentials / drug effects
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Patch-Clamp Techniques
  • Purinergic P2 Receptor Antagonists*
  • Quinolinium Compounds
  • Rats
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2X7
  • Species Specificity
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Transfection
  • Xanthenes


  • AZ 11645373
  • Aniline Compounds
  • Anti-Inflammatory Agents
  • Benzoxazoles
  • Fluo 4
  • Fluorescent Dyes
  • Imides
  • Interleukin-1beta
  • Lipopolysaccharides
  • P2RX7 protein, human
  • P2rx7 protein, rat
  • Purinergic P2 Receptor Antagonists
  • Quinolinium Compounds
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X7
  • Thiazoles
  • Xanthenes
  • YO-PRO 1
  • 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
  • Adenosine Triphosphate