title: Synthesis and structure-activity relationships of uracil nucleotide derivatives and analogues as agonists at human P2Y2, P2Y4, and P2Y6 receptors.
abstract: A series of UTP, UDP, and UMP derivatives and analogues were synthesized and evaluated at the human pyrimidinergic P2Y receptor subtypes P2Y2, P2Y4, and P2Y6 stably expressed in 1321N1 astrocytoma cells. Substituents at N3 of UTP were poorly tolerated by P2Y2 and P2Y4 receptors. In contrast, a large phenacyl substituent at N3 of UDP was well tolerated by the P2Y6 receptor, yielding a potent and selective P2Y6 receptor agonist (3-phenacyl-UDP, EC50=70 nM, >500-fold selective). The most potent and selective P2Y2 receptor agonist of the present series was 2-thio-UTP (EC50=50 nM, >or=30-fold selective vs P2Y4 and P2Y6). All modifications at the uracil base of UTP led to a decrease in potency at the P2Y4 receptor. A beta,gamma-dichloromethylene modification in the triphosphate chain of 5-bromo-UTP was tolerated by all three receptor subtypes, thus opening up a new strategy to obtain ectonucleotide diphosphohydrolase- and phosphatase-resistant P2Y2, P2Y4, and P2Y6 receptor agonists.
authors.affiliation: Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: El-Tayeb
authors.forename: Aidong
authors.initials: A
authors.lastname: Qi
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D058910:Purinergic P2 Receptor Agonists; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D013329:Structure-Activity Relationship; D014500:Uracil Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D014530:Uridine Diphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C517059:7,8-dihydro-8-ethyl-2-(4-bicyclo(2.2.2)octan-1-ol)-4-propyl-1H-imidazo(2,1-i)purin-5(4H)-one; D001643:Bridged Bicyclo Compounds; D007295:Inositol Phosphates; C546385:P2RY2 protein, human; D058910:Purinergic P2 Receptor Agonists; D011687:Purines; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D014500:Uracil Nucleotides; C104749:purinoceptor P2Y4; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate; D014542:Uridine Monophosphate; D014544:Uridine Triphosphate