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4-Alkyloxyimino derivatives of pyrimidine nucleotides display high potency as agonists of certain G protein-coupled P2Y receptors (P2YRs). In an effort to functionalize a P2Y 6 R agonist for fluorescent labeling, we probed two positions ( N  4 and γ-phosphate of cytidine derivatives) with various functional groups, including alkynes for click chemistry. Functionalization of extended imino substituents at the 4 position of the pyrimidine nucleobase of CDP preserved P2Y 6 R potency generally better than γ-phosphoester formation in CTP derivatives. Fluorescent Alexa Fluor 488 conjugate 16 activated the human P2Y 6 R expressed in 1321N1 human astrocytoma cells with an EC 50 of 9 nM, and exhibited high selectivity for this receptor over other uridine nucleotide-activated P2Y receptors. Flow cytometry detected specific labeling with 16 to P2Y 6 R-expressing but not to wild-type 1321N1 cells. Additionally, confocal microscopy indicated both internalized 16 ( t  1/2 of 18 min) and surface-bound fluorescence. Known P2Y 6 R ligands inhibited labeling. Theoretical docking of 16 to a homology model of the P2Y 6 R predicted electrostatic interactions between the fluorophore and extracellular portion of TM3. Thus, we have identified the N  4 -benzyloxy group as a structurally permissive site for synthesis of functionalized congeners leading to high affinity molecular probes for studying the P2Y 6 R.

4-Alkyloxyimino-cytosine nucleotides: tethering approaches to molecular probes for the P2Y6 receptor