Synthesis and Structure-Activity Relationships of Uracil Nucleotide Derivatives and Analogues as Agonists at Human P2Y2, P2Y4, and P2Y6 Receptors
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- 作者：Ali El-Tayeb ; Aidong Qi ; Christa E. Mü ; ller
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：November 30, 2006
- 年：2006
- 卷：49
- 期：24
- 页码：7076 - 7087
- 全文大小：280K
- 年卷期：v.49,no.24(November 30, 2006)
- ISSN：1520-4804
文摘
A series of UTP, UDP, and UMP derivatives and analogues were synthesized and evaluated at the humanpyrimidinergic P2Y receptor subtypes P2Y2, P2Y4, and P2Y6 stably expressed in 1321N1 astrocytoma cells.Substituents at N3 of UTP were poorly tolerated by P2Y2 and P2Y4 receptors. In contrast, a large phenacylsubstituent at N3 of UDP was well tolerated by the P2Y6 receptor, yielding a potent and selective P2Y6receptor agonist (3-phenacyl-UDP, EC50 = 70 nM, >500-fold selective). The most potent and selectiveP2Y2 receptor agonist of the present series was 2-thio-UTP (EC50 = 50 nM, 
30-fold selective vs P2Y4and P2Y6). All modifications at the uracil base of UTP led to a decrease in potency at the P2Y4 receptor.A 
,
-dichloromethylene modification in the triphosphate chain of 5-bromo-UTP was tolerated by all threereceptor subtypes, thus opening up a new strategy to obtain ectonucleotide diphosphohydrolase- andphosphatase-resistant P2Y2, P2Y4, and P2Y6 receptor agonists.
30-fold selective vs P2Y4and P2Y6). All modifications at the uracil base of UTP led to a decrease in potency at the P2Y4 receptor.A ,-dichloromethylene modification in the triphosphate chain of 5-bromo-UTP was tolerated by all threereceptor subtypes, thus opening up a new strategy to obtain ectonucleotide diphosphohydrolase- andphosphatase-resistant P2Y2, P2Y4, and P2Y6 receptor agonists.