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

Younis Baqi, Ralf Hausmann, Christiane Rosefort, Jürgen Rettinger, Günther Schmalzing, Christa E. Müller

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)


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 8 6 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 24612); 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.

Original languageEnglish
Pages (from-to)817-830
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number3
Publication statusPublished - Feb 10 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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