ArticleJournal of medicinal chemistry2010
Pyrimidine ribonucleotides with enhanced selectivity as P2Y(6) receptor agonists: novel 4-alkyloxyimino, (S)-methanocarba, and 5'-triphosphate gamma-ester modifications.
Article in Journal of medicinal chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- Applications of artificial intelligence in drug discovery for neurological diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Machine learning-aided search for ligands of P2YPurinergic signalling · 2024Article
- Pharmacological characterization of P2Y receptor subtypes - an update.Purinergic signalling · 2024Review
- Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets.RSC medicinal chemistry · 2021Review
- Structure-activity relationships of pyrimidine nucleotides containing a 5'-α,β-methylene diphosphonate at the P2YBioorganic & medicinal chemistry letters · 2021Article
- Structure activity relationship of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives as P2YBioorganic & medicinal chemistry letters · 2021Article
- Survey of ribose ring pucker of signaling nucleosides and nucleotides.Nucleosides, nucleotides & nucleic acids · 2020Article
- Overview of Biologically Active Nucleoside Phosphonates.Frontiers in chemistry · 2020Review
- Repurposing of a Nucleoside Scaffold from Adenosine Receptor Agonists to Opioid Receptor Antagonists.ACS omega · 2018Article
- Polypharmacology of conformationally locked methanocarba nucleosides.Drug discovery today · 2017Review
- Pyrimidine Nucleotides Containing a (S)-Methanocarba Ring as P2YMedChemComm · 2017Article
- South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase.Journal of medicinal chemistry · 2016Article
- Thymidine 5'-O-monophosphorothioate induces HeLa cell migration by activation of the P2Y6 receptor.Purinergic signalling · 2016Article
- Design, synthesis, pharmacological characterization of a fluorescent agonist of the P2Y₁₄ receptor.Bioorganic & medicinal chemistry letters · 2015Article
- Nucleotides Acting at P2Y Receptors: Connecting Structure and Function.Molecular pharmacology · 2015Review
- Enhancement of glucose uptake in mouse skeletal muscle cells and adipocytes by P2Y6 receptor agonists.PloS one · 2014Article
- Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches.MedChemComm · 2013Article
- The Concise Guide to PHARMACOLOGY 2013/14: G protein-coupled receptors.British journal of pharmacology · 2013Article
- 4-Alkyloxyimino-cytosine nucleotides: tethering approaches to molecular probes for the P2YMedChemComm · 2013Article
- Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates.Journal of medicinal chemistry · 2013Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
The P2Y(6) receptor is a cytoprotective G-protein-coupled receptor (GPCR) activated by UDP (EC(50) = 0.30 microM). We compared and combined modifications to enhance P2Y(6) receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications such as alpha,beta-methylene and extension of the terminal phosphate group into gamma-esters of UTP analogues. The conformationally constrained (S)-methanocarba-UDP is a full agonist (EC(50) = 0.042 microM). 4-Methoxyimino modification of pyrimidine enhanced P2Y(6), preserved P2Y(2) and P2Y(4), and abolished P2Y(14) receptor potency, in the appropriate nucleotide. N(4)-Benzyloxy-CDP (15, MRS2964) and N(4)-methoxy-Cp(3)U (23, MRS2957) were potent, selective P2Y(6) receptor agonists (EC(50) of 0.026 and 0.012 microM, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-gamma-aryl and cycloalkyl phosphoesters displayed only intermediate P2Y(6) receptor potency but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N(4)-methoxycytidine 5'-triphospho-gamma-[1]glucose were active (EC(50) of 2.47 and 0.18 microM, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y(6) receptor agonists may be enhanced by modest structural changes.
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