PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
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.
评估和优化与反应性蓝 2 相关的蒽醌衍生物在 P2X2 受体上产生了第一个有效且选择性的 P2X2 受体拮抗剂。这些化合物在表达大鼠 P2X2 受体的非洲爪蟾卵母细胞中被测试了对 ATP（10 μM）介导电流的抑制作用。最有效的拮抗剂是 1-氨基-4-[3-(4,6-二氯[1,3,5]三嗪-2-基氨基)苯基氨基]-9,10-二氧代-9,10-二氢蒽-2-磺酸钠（63，PSB-10211，IC50 86 nM）和 1-氨基-4-[3-(4,6-二氯[1,3,5]三嗪-2-基氨基)-4-磺基苯基氨基]-9,10-二氧代-9,10-二氢蒽-2-磺酸钠（57，PSB-1011，IC50 79 nM）。化合物 57 表现出竞争性作用机制（pA2 7.49）。它对 P2X4、P2X7 和几种研究的 P2Y 受体亚型（P2Y（2,4,6,12））的选择性 >100 倍；对 P2X1 和 P2X3 受体的选择性适中（>5 倍）。化合物 57 在同型 P2X2 受体上的效力比在异型 P2X2/3 受体上高 13 倍以上。一些蒽醌衍生物被发现是 P2X2 受体上 ATP 效应的正调节剂，例如 1-氨基-4-（3-苯氧基苯基氨基）-9,10-二氧代-9,10-二氢蒽-2-磺酸钠（51，PSB-10129，EC50 489 nM），它导致 ATP 引发的电流增加约 3 倍。
