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J Med Chem. 2010 Jan 14;53(1):471-80. doi: 10.1021/jm901432g.

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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Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.


Uridine-5'-diphosphoglucose (UDPG) activates the P2Y(14) receptor, a neuroimmune system GPCR. P2Y(14) receptor tolerates glucose substitution with small alkyl or aryl groups or its truncation to uridine 5'-diphosphate (UDP), a full agonist at the human P2Y(14) receptor expressed in HEK-293 cells. 2-Thiouracil derivatives displayed selectivity for activation of the human P2Y(14) vs the P2Y(6) receptor, such as 2-thio-UDP 4 (EC(50) = 1.92 nM at P2Y(14), 224-fold selectivity vs P2Y(6)) and its beta-propyloxy ester 18. EC(50) values of the beta-methyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. beta-tert-Butyl ester of 4 was 11-fold more potent than UDPG, but beta-aryloxy or larger, branched beta-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 P2Y(14) receptor agonist activity. alpha,beta-Methylene and difluoromethylene groups were well tolerated at the P2Y(14) receptor and are expected to provide enhanced stability in biological systems. alpha,beta-Methylene-2-thio-UDP 11 (EC(50) = 0.92 nM) was 2160-fold selective versus P2Y(6). Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y(14) receptor.

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