Human P2Y14 Receptor Agonists: Truncation of the Hexose Moiety of Uridine-5′-Diphosphoglucose and Its Replacement with Alkyl and Aryl Groups
| Autor: | Matthew O. Barrett, Arijit Das, Kenneth A. Jacobson, Hyojin Ko, T. Kendall Harden, Lauren E. Burianek |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Purinergic P2 Receptor Agonists
Uridine Diphosphate Glucose Agonist Ribonucleotide Alkylation medicine.drug_class Stereochemistry Molecular Conformation Receptor agonist activity Article Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Humans Structure–activity relationship Nucleotide Receptor Cells Cultured Hexoses G protein-coupled receptor chemistry.chemical_classification Dose-Response Relationship Drug Receptors Purinergic P2 Stereoisomerism Uridine chemistry Drug Design Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 53:471-480 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|