Pyrimidine nucleotides with 4-alkyloxyimino and terminal tetraphosphate δ-ester modifications as selective agonists of the P2Y4 receptor

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NIDDK	BIOCHEM/CHEM-16

* FARE Award Winner

Authors

• H Maruoka
• MO Barrett
• S de Castro
• N Kim
• S Costanzi
• KT Harden
• KA Jacobson
• MPS Jayasekara

Abstract

The P2Y2 and P2Y4 receptors are G protein-coupled receptors (GPCRs), activated by UTP and dinucleoside tetraphosphates, which are widely distributed in epithelial cells, smooth muscle, and other tissues. These subtypes are difficult to distinguish pharmacologically, due to lack of potent and selective ligands. Previously, agonist ligands selective for P2Y2 but not P2Y4 receptors have been reported. We varied structurally the phosphate and uracil moieties in analogues of pyrimidine nucleoside 5′-triphosphates and 5′-tetraphosphate esters, which were evaluated in stimulation of phospholipase C in stably transfected 1321N1 astrocytoma cells. The 4 position of cytidine was appended with alkyloxy groups, which enhanced P2Y4 receptor potency. N4-(Phenylpropoxy)-CTP (MRS4062), Up4-[1]3′-deoxy-3′-fluoroglucose (MRS2927) and N4-(Phenylethoxy)-CTP (MRS4061) were selective for the P2Y4 receptor with EC50 values of 23, 62 and 73 nM, respectively. Molecular docking of selected analogues at the P2Y2 and P2Y4 receptors was performed. Thus, the potency, selectivity, and stability of extended uridine tetraphosphate derivatives may be modulated by distal structural changes, and we have identified the first reported P2Y4 receptor agonists.

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