TY - JOUR
T1 - Discovery of potent competitive antagonists and positive modulators of the P2X2 receptor
AU - Baqi, Younis
AU - Hausmann, Ralf
AU - Rosefort, Christiane
AU - Rettinger, Jürgen
AU - Schmalzing, Günther
AU - Müller, Christa E.
PY - 2011/2/10
Y1 - 2011/2/10
N2 - 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.
AB - 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.
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U2 - 10.1021/jm1012193
DO - 10.1021/jm1012193
M3 - Article
C2 - 21207957
AN - SCOPUS:79851471254
SN - 0022-2623
VL - 54
SP - 817
EP - 830
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -