ArticleBiochemical pharmacology2006
Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5'-triphosphate analogues at the human P2Y2 and P2Y4 receptors.
Article in Biochemical pharmacology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 53 citations in OpenAlex.
- Advances in nucleotide-based P2Y₁ antagonism: implications for cardiovascular therapeutics.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Article
- Structural insight into the self-activation and G-protein coupling of P2Y2 receptor.Cell discovery · 2025Article
- Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates.Nature chemistry · 2024Article
- Review
- P2Y receptors for extracellular nucleotides: Contributions to cancer progression and therapeutic implications.Biochemical pharmacology · 2021Review
- Article
- ATP evokes CaJournal of neurochemistry · 2017Article
- 4-Alkyloxyimino derivatives of uridine-5'-triphosphate: distal modification of potent agonists as a strategy for molecular probes of P2Y2, P2Y4, and P2Y6 receptors.Journal of medicinal chemistry · 2014Article
- 4-Alkyloxyimino-cytosine nucleotides: tethering approaches to molecular probes for the P2YMedChemComm · 2013Article
- P2Y receptor subtypes evoke different Ca2+ signals in cultured aortic smooth muscle cells.Purinergic signalling · 2012Article
- Molecular Structure of P2Y Receptors: Mutagenesis, Modeling, and Chemical Probes.Wiley interdisciplinary reviews. Membrane transport and signaling · 2012Article
- P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential.CNS & neurological disorders drug targets · 2012Review
- G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions.Purinergic signalling · 2012Review
- Pyrimidine nucleotides with 4-alkyloxyimino and terminal tetraphosphate δ-ester modifications as selective agonists of the P2Y(4) receptor.Journal of medicinal chemistry · 2011Article
- Adenine nucleotide control of coronary blood flow during exercise.American journal of physiology. Heart and circulatory physiology · 2010Article
- Ca(2+) signalling by P2Y receptors in cultured rat aortic smooth muscle cells.British journal of pharmacology · 2010Article
- P2Y nucleotide receptors: promise of therapeutic applications.Drug discovery today · 2010Review
- Development of selective agonists and antagonists of P2Y receptors.Purinergic signalling · 2009Article
- Development of selective high affinity antagonists, agonists, and radioligands for the P2Y1 receptor.Combinatorial chemistry & high throughput screening · 2008Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
With the long-term goal of developing receptor subtype-selective high affinity agonists for the uracil nucleotide-activated P2Y receptors we have carried out a series of structure activity and molecular modeling studies of the human P2Y2 and P2Y4 receptors. UTP analogues with substitutions in the 2'-position of the ribose moiety retained capacity to activate both P2Y2 and P2Y4 receptors. Certain of these analogues were equieffective for activation of both receptors whereas 2'-amino-2'-deoxy-UTP exhibited higher potency for the P2Y2 receptor and 2'-azido-UTP exhibited higher potency for the P2Y4 receptor. 4-Thio substitution of the uracil base resulted in a UTP analogue with increased potency relative to UTP for activation of both the P2Y2 and P2Y4 receptors. In contrast, 2-thio substitution and halo- or alkyl substitution in the 5-position of the uracil base resulted in molecules that were 3-30-fold more potent at the P2Y2 receptor than P2Y4 receptor. 6-Aza-UTP was a P2Y2 receptor agonist that exhibited no activity at the P2Y4 receptor. Stereoisomers of UTPalphaS and 2'-deoxy-UTPalphaS were more potent at the P2Y2 than P2Y4 receptor, and the R-configuration was favored at both receptors. Molecular docking studies revealed that the binding mode of UTP is similar for both the P2Y2 and P2Y4 receptor binding pockets with the most prominent dissimilarities of the two receptors located in the second transmembrane domain (V90 in the P2Y2 receptor and I92 in the P2Y4 receptor) and the second extracellular loop (T182 in the P2Y2 receptor and L184 in the P2Y4 receptor). In summary, this work reveals substitutions in UTP that differentially affect agonist activity at P2Y2 versus P2Y4 receptors and in combination with molecular modeling studies should lead to chemical synthesis of new receptor subtype-selective drugs.
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