4145-46-4Relevant academic research and scientific papers
Structural modifications of UMP, UDP, and UTP leading to subtype-selective agonists for P2Y2, P2Y4, and P2Y6 receptors
El-Tayeb, Ali,Qi, Aidong,Nicholas, Robert A.,Müller, Christa E.
, p. 2878 - 2890 (2011/06/24)
A large series of derivatives and analogues of the uracil nucleotides UMP, UDP, and UTP with modifications in various positions of the uracil moiety and/or the phosphate groups were synthesized and evaluated at human P2Y2, P2Y4, and P2Y6 receptors. 2-(Ar)alkylthio substitution of UMP and UDP was best tolerated by the P2Y2 receptor. 2-Phenethylthio-UMP (13e) showed an EC50 value of 1.3 μM at P2Y2 and >70-fold selectivity versus P2Y4 and P2Y 6 receptors. Substitution of the 2-keto group in UMP by NH (13g, iso-CMP) resulted in the first potent and selective P2Y4 agonist (EC50 4.98 μM, >20-fold selective vs P2Y2 and P2Y6). In contrast, replacement of the 2-keto function in UDP by NH yielded a potent P2Y2 agonist (12g, iso-CDP, EC50 = 0.604 μM, >100-fold selective). In an attempt to obtain metabolically stable UTP analogues, β,γ-dichloro- and β,γ-difluoro-methylene-UTP derivatives were synthesized. The triphosphate modifications were much better tolerated by P2Y2, and in some cases also by P2Y6, than by P2Y4 receptors. 4-Thio-β,γ-difluoromethylene-UTP (14g) was a potent P2Y2 agonist with an EC50 value of 0.134 μM and >50-fold selectivity. N3-Phenacyl-β,γ-dichloromethylene- UTP (14b) proved to be a potent P2Y6 receptor agonist (EC 50 0.142 μM) with high selectivity versus P2Y4 (50-fold) and moderate selectivity versus P2Y2 receptors (6-fold).
Human P2Y14 receptor agonists: Truncation of the hexose moiety of uridine-5′-diphosphoglucose and its replacement with alkyl and aryl groups
Das, Arijit,Ko, Hyojin,Burianek, Lauren E.,Barrett, Matthew O.,Harden, T. Kendall,Jacobson, Kenneth A.
scheme or table, p. 471 - 480 (2010/05/02)
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 at the 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 nMat P2Y14, 224-fold selectivity vs P2Y6) and its β-propyloxy ester 18. EC50 values of the β-methyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. β-tert-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.
