Human P2Y(14) receptor agonists: truncation of the hexose moiety of uridine-5'-diphosphoglucose and its replacement with alkyl and aryl groups.
Human P2Y(14) receptor agonists: truncation of the hexose moiety of uridine-5'-diphosphoglucose and its replacement with alkyl and aryl groups.
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DOI：
10.1021/jm901432g
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发表时间：
2010-01-14
影响因子：
7.3
通讯作者：
Jacobson, Kenneth A.
中科院分区：
文献类型：
--
作者：
Das, Arijit;Ko, Hyojin;Burianek, Lauren E.;Barrett, Matthew O.;Harden, T. Kendall;Jacobson, Kenneth A.
尿苷-5′-二磷酸葡萄糖（UDPG）激活P2Y14受体，一种神经免疫系统GPCR。P2Y14受体耐受葡萄糖被小烷基或芳基取代或截断为尿苷-5 ' -二磷酸（UDP），这是一种在HEK-293细胞中表达的完全激动剂人P2Y14受体。2-硫脲嘧啶衍生物对人P2Y14和P2Y6受体的激活具有选择性，如2-硫- udp 4（在P2Y14处EC50为1.92 nM，选择性为P2Y6的224倍）及其β-丙氧基酯18。UDP β-甲酯及其2-硫代类似物的EC50分别为2730 nM和56 nM。β- 4 -t-丁基酯的效力是UDPG的11倍，但β-芳氧基或更大的支链β-烷基酯，如环己基，效力较弱。用刚性的北或南甲醇羰基（双环[3.1.0]己烷）取代UDP的核糖会破坏P2Y14受体激动剂的活性。α、β-亚甲基和二氟乙烯基团在P2Y14受体上具有良好的耐受性，并有望在生物系统中提供更高的稳定性。α，β-亚甲基-2-硫代- udp 11 （EC50 0.92 nM）选择性为P2Y6的2160倍。因此，这些核苷酸及其同源物可以作为检测和表征P2Y14受体的重要药理学探针。
Uridine-5′-diphosphoglucose (UDPG) activates the P2Y14 receptor, a neuroimmune system GPCR. P2Y14 receptor tolerates glucose substitution with small alkyl or aryl groups or its truncation to uridine-5′-diphosphate (UDP), a full agonist human P2Y14 receptor expressed in HEK-293 cells. 2-Thiouracil derivatives displayed selectivity for activation of the human P2Y14 vs. the P2Y6 receptor, such as 2-thio-UDP 4 (EC50 1.92 nM at P2Y14, 224-fold selectivity vs. P2Y6) and its β-propyloxy ester 18. EC50 of β-methyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. β-t-Butyl ester of 4 was 11-fold more potent than UDPG, but β-aryloxy or larger, branched β-alkyl esters, such as cyclohexyl, were less potent. Ribose replacement of UDP with a rigid North or South methanocarba (bicyclo[3.1.0]hexane) group abolished P2Y14 receptor agonist activity. α,β-Methylene and difluoromethylene groups were well tolerated at the P2Y14 receptor and are expected to provide enhanced stability in biological systems. α,β-Methylene-2-thio-UDP 11 (EC50 0.92 nM) was 2160-fold selective versus P2Y6. Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y14 receptor.
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影响因子：
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