5-substituted UTP derivatives as P2Y(2) receptor agonists

A series of 5-alkyl-substituted UTP derivatives, which had been synthesized previously with a moderate degree of purity, was resynthesized, purified, and characterized. Synthetic and purification procedures were optimized. Ne w spectroscopic data, including C-13- and P-31 NMR data, are presented. Pho sphorylation reactions yielded a number of side products, such as the 2'-, 3'-, and 5'-monophosphates, the 2',3'-cyclic monophosphates, and the 2',3'- cyclic phosphates of the 5'-triphosphates. Furthermore, raw products were c ontaminated with inorganic phosphates, including cyclometatriphosphate, pho sphate, and pyrophosphate. The uracil nucleotides were investigated for the ir potency to increase intracellular calcium concentrations by stimulation of P2Y(2) receptors (P2Y(2)R) on NG108-15 cells, a mouse neuroblastoma x gl ioma cell line, and in human basal epithelial airway cells, including a cys tic fibrosis (CF/T43) cell line. UTP exhibited EC50 values of ca. 1 mu M (i n NG108-15 cells) and of 0.1 mu M (in CF/T43 cells), respectively. 5-Substi tuted UTP derivatives were agonists at the P2Y(2)R, but were less potent th an UTP. 5-Ethyl-UTP, for example, exhibited an EC50 value of 99 mu M at P2Y (2)R of NG108-15 cells and proved to be a full agonist. With increasing vol ume of the 5-substituent of UTP derivatives, P2Y(2) activity decreased. (C) 1999 Editions scientifiques et medicales Elsevier SAS.