Pyrimidine Nucleotides with 4-Alkyloxyimino and Terminal Tetraphosphate delta-Ester Modifications as Selective Agonists of the P2Y(4) Receptor

• Published in: Journal of medicinal chemistry Vol. 54; no. 12; pp. 4018 - 4033
• Main Authors: Maruoka, Hiroshi, Jayasekara, M. P. Suresh, Barrett, Matthew O., Franklin, Derek A., de Castro, Sonia, Kim, Nathaniel, Costanzi, Stefano, Harden, T. Kendall, Jacobson, Kenneth A.
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 23.06.2011
• Subjects: Amino Acid Sequence; Cell Line, Tumor; Chemistry, Medicinal; Drug Stability; Esters; Humans; Life Sciences & Biomedicine; Ligands; Models, Molecular; Molecular Sequence Data; Pharmacology & Pharmacy; Purinergic P2 Receptor Agonists - chemical synthesis; Purinergic P2 Receptor Agonists - chemistry; Purinergic P2 Receptor Agonists - pharmacology; Radioligand Assay; Receptors, Purinergic P2 - metabolism; Science & Technology; Sequence Homology, Amino Acid; Structure-Activity Relationship; Uracil Nucleotides - chemical synthesis; Uracil Nucleotides - chemistry; Uracil Nucleotides - pharmacology; MUTAGENESIS; ACTIVATION; EXTRACELLULAR LOOPS; ANALOGS; LIGAND RECOGNITION; PHARMACOLOGY; ARCHITECTURE; ANTAGONISTS; DERIVATIVES; URACIL NUCLEOTIDES
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm101591j

P2Y(2) and P2Y(4) receptors are G protein-coupled receptors, activated by UTP and dinudeoside tetraphosphates, which are difficult to distinguish pharmacologically for lack of potent and selective ligands. We structurally varied phosphate and uracil moieties in analogues of pyrimidine nucleoside 5'-triphosphates and 5'-tetraphosphate esters. P2Y(4) receptor potency in phospholipase C stimulation in transfected 1321N1 human astrocytoma cells was enhanced in N-4-alkyloxycytidine derivatives. OH groups on a terminal delta-glucose phosphoester of uridine 5'-tetraphosphate were inverted or substituted with H or F to probe H-bonding effects. N-4-(Phenylpropoxy)-CTP 16 (MRS4062), Up(4)-[1]3'-deoxy-3'-fluoroglucose 34 (MRS2927), and N-4-(phenylethoxy)-CTP 15 exhibit >= 10-fold selectivity for human P2Y(4) over P2Y(2) and P2Y(6) receptors (EC50 values 23, 62, and 73 nM, respectively). delta-3-Chlorophenyl phosphoester 21 of Up(4) activated P2Y(2) but not P2Y(4) receptor. Selected nucleotides tested for chemical and enzymatic stability were much more stable than UTP. Agonist docking at CXCR4-based P2Y(2) and P2Y(4) receptor models indicated greater steric tolerance of N-4-phenylpropoxy group at P2Y(4). Thus, distal structural changes modulate potency, selectivity, and stability of extended uridine tetraphosphate derivatives, and we report the first P2Y(4) receptor-selective agonists.