Human P2Y14 Receptor Agonists: Truncation of the Hexose Moiety of Uridine-5′-Diphosphoglucose and Its Replacement with Alkyl and Aryl Groups

Uridine-5'-diphosphoglucosc (UDPG) activates the P2Y(14) receptor, a neuroinimune system GPCR. P2Y(14) receptor tolerates glucose substitution with sinall 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 P2Y6 receptor, such as 2-thio-UDP4 (EC5() = 1.92 nM at P2Y(14), 224-fold selectivity vs P2Y6)and itsfl-propyloxy ester 18. EC,,() values of tlie -niethyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. -Iert-Butyl ester of 4 was I I-fold more potent than UDPG, but P-aryloxy or larger, branched -alkyl esters, such as cyclohexyl, were less potent. Ribose replacement of UDP with a rigid North or South rriethanocarba (bicyclo[3. 1.0]hexane) group abolished P2Y(14) receptor agonist activity. ci,p-Methylene and difluoromethylene groups were well tolerated at the P2Y(14) receptor and are expected to provide enhanced stability in biological systems. a,beta-Methylene-2-thio-UDP 11 (EC50 = 0.92 nM) was 2160fold selective versus P2Y6. Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y(14) receptor-