Boranophosphate isoster controls P2Y-receptor subtype selectivity and metabolic stability of dinucleoside polyphosphate analogues.
Boranophosphate isoster controls P2Y-receptor subtype selectivity and metabolic stability of dinucleoside polyphosphate analogues.
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硼烷磷酸等排物控制二核苷多磷酸类似物的 P2Y 受体亚型选择性和代谢稳定性。
DOI：
10.1021/jm2013198
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发表时间：
2012
影响因子：
7.3
通讯作者：
Fischer,Bilha
中科院分区：
文献类型：
--
作者：
Yelovitch,Shir;Camden,Jean;Weisman,GaryA;Fischer,Bilha
多磷酸二核苷（NpnN′）通过P2受体（P2 Rs）发挥其生理作用。NpnN′是有吸引力的候选药物，因为与最常见的P2 R配体核苷酸相比，它们提供更好的稳定性和特异性。为了进一步改善Npn N ′的激动剂性质，我们合成了N和N′为A或U，Pα或Pβ磷酸基团被硼磷酸取代的新型二核苷多磷酸等排体，分别表示为Npn（α-B）N′或Npn（β-B）N′（n= 3，4）。在tP 2 Y1、hP 2 Y2、hP 2 Y 4和rP 2 Y 6受体上评价了Npn（α/β-B）N′类似物的效力。最有效的P2 Y1 R和P2 Y 6 R激动剂分别是Up 4（β-B）A（A异构体，EC 50为0.5 μM，2-SMe-ADP为0.004 μM）和Up3（α-B）U（B异构体，EC 50为0.3 μM，UDP为0.2 μM）。受体亚型选择性受NpnN′多磷酸链上硼基部分的位置和核碱基的类型控制。此外，Npn（α/β-B）N′对e-NPP 1水解的抗性是相应Npn N ′类似物的22倍。总之，Up 4（β-B）A和Up3（α-B）U分别是有效的、稳定的和高选择性的P2 Y1和P2 Y 6受体激动剂。
Dinucleoside polyphosphates, NpnN′, exert their physiological effects via P2 receptors (P2Rs). NpnN′ are attractive drug candidates as they offer better stability and specificity compared to nucleotides, the most common P2R ligands. To further improve the agonist properties of NpnN′, we synthesized novel isosters of dinucleoside polyphosphates where N and N′ are A or U and where the Pα or Pβ phosphate groups are replaced by boranophosphate, denoted as Npn(α-B)N′ or Npn(β-B)N′ (n= 3, 4), respectively. The potency of Npn(α/β-B)N′ analogues was evaluated at tP2Y1, hP2Y2, hP2Y4, and rP2Y6receptors. The most potent P2Y1R and P2Y6R agonists were the Up4(β-B)A (A isomer, EC50of 0.5 μM vs 0.004 μM for 2-SMe-ADP) and Up3(α-B)U (B isomer, EC50of 0.3 μM vs 0.2 μM for UDP), respectively. The receptor subtype selectivity is controlled by the position of the borano moiety on the NpnN′ polyphosphate chain and the type of the nucleobase. In addition, Npn(α/β-B)N′ proved ∼22-fold more resistant to hydrolysis by e-NPP1, as compared to the corresponding NpnN′ analogues. In summary, Up4(β-B)A and Up3(α-B)U are potent, stable, and highly selective P2Y1and P2Y6receptor agonists, respectively.