Discovery of potent competitive antagonists and positive modulators of the P2X2 receptor

J Med Chem. 2011 Feb 10;54(3):817-30. doi: 10.1021/jm1012193. Epub 2011 Jan 5.


Evaluation and optimization of anthraquinone derivatives related to Reactive Blue 2 at P2X2 receptors yielded the first potent and selective P2X2 receptor antagonists. The compounds were tested for inhibition of ATP (10 μM) mediated currents in Xenopus oocytes expressing the rat P2X2 receptor. The most potent antagonists were sodium 1-amino-4-[3-(4,6-dichloro[1,3,5]triazine-2-ylamino)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (63, PSB-10211, IC(50) 86 nM) and disodium 1-amino-4-[3-(4,6-dichloro[1,3,5]triazine-2-ylamino)-4-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (57, PSB-1011, IC(50) 79 nM). Compound 57 exhibited a competitive mechanism of action (pA(2) 7.49). It was >100-fold selective versus P2X4, P2X7, and several investigated P2Y receptor subtypes (P2Y(2,4,6,12)); selectivity versus P2X1 and P2X3 receptors was moderate (>5-fold). Compound 57 was >13-fold more potent at the homomeric P2X2 than at the heteromeric P2X2/3 receptor. Several anthraquinone derivatives were found to act as positive modulators of ATP effects at P2X2 receptors, for example, sodium 1-amino-4-(3-phenoxyphenylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (51, PSB-10129, EC(50) 489 nM), which led to about a 3-fold increase in the ATP-elicited current.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthraquinones / chemical synthesis*
  • Anthraquinones / chemistry
  • Anthraquinones / pharmacology
  • Female
  • Humans
  • Oocytes / drug effects
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Purinergic P2X Receptor Antagonists / chemical synthesis*
  • Purinergic P2X Receptor Antagonists / chemistry
  • Purinergic P2X Receptor Antagonists / pharmacology
  • Rats
  • Receptors, Purinergic P2X2 / metabolism*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Triazines / chemistry
  • Xenopus laevis


  • 1-amino-4-(3-(4,6-dichloro(1,3,5)triazine-2-ylamino)phenylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate
  • Anthraquinones
  • Purinergic P2X Receptor Antagonists
  • Receptors, Purinergic P2X2
  • Recombinant Proteins
  • Triazines
  • Cibacron Blue F 3GA