ArticleBioorganic & medicinal chemistry2004
Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-alpha-threofuranosyl ring systems: interactions with P2Y receptors.
Article in Bioorganic & medicinal chemistry, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 30 citations in OpenAlex.
- Residue Interaction Network Reveals Allosteric Pathways Linking Orthosteric and Intracellular Sites in Class A GPCRs.Journal of chemical information and modeling · 2026Article
- Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets.RSC medicinal chemistry · 2021Review
- Synthesis of bridged tricyclo[5.2.1.0Nature communications · 2020Article
- Virtual screening leads to the discovery of novel non-nucleotide P2Y₁ receptor antagonists.Bioorganic & medicinal chemistry · 2012Article
- Functionalized congeners of P2Y1 receptor antagonists: 2-alkynyl (N)-methanocarba 2'-deoxyadenosine 3',5'-bisphosphate analogues and conjugation to a polyamidoamine (PAMAM) dendrimer carrier.Bioconjugate chemistry · 2010Article
- Structure-activity relationships of uridine 5'-diphosphate analogues at the human P2Y6 receptor.Journal of medicinal chemistry · 2006Article
- International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy.Pharmacological reviews · 2006Review
- Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5'-triphosphate analogues at the human P2Y2 and P2Y4 receptors.Biochemical pharmacology · 2006Article
- MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y1 receptor with strong antithrombotic activity in mice.The Journal of pharmacology and experimental therapeutics · 2006Article
- Agonists and antagonists for P2 receptors.Novartis Foundation symposium · 2006Review
- Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preference.Journal of medicinal chemistry · 2005Article
- Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality.Organic & biomolecular chemistry · 2005Article
- Purine receptors: GPCR structure and agonist design.Molecular interventions · 2004Article
- Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling.Journal of computer-aided molecular designArticle
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Authors and funding
10 authors at 4 institutions in 3 countries.
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Abstract
The ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y(1) receptor has been successfully substituted with a rigid methanocarba ring system, leading to the conclusion that the North (N) ring conformation is preferred in receptor binding. Similarly, at P2Y(2) and P2Y(4) receptors, nucleotides constrained in the (N) conformation interact equipotently with the corresponding ribosides. We now have synthesized and examined as P2Y receptor ligands nucleotide analogues substituted with two novel ring systems: (1) a (N) locked-carbocyclic (cLNA) derivative containing the oxabicyclo[2.2.1]heptane ring system and (2) l-alpha-threofuranosyl derivatives. We have also compared potencies and preferred conformations of these nucleotides with the known anhydrohexitol-containing P2Y(1) receptor antagonist MRS2283. A cLNA bisphosphate derivative MRS2584 21 displayed a K(i) value of 22.5 nM in binding to the human P2Y(1) receptor, and antagonized the stimulation of PLC by the potent P2Y(1) receptor agonist 2-methylthio-ADP (30 nM) with an IC(50) of 650 nM. The parent cLNA nucleoside bound only weakly to an adenosine receptor (A(3)). Thus, this ring system afforded some P2Y receptor selectivity. A l-alpha-threofuranosyl bisphosphate derivative 9 displayed an IC(50) of 15.3 microM for inhibition of 2-methylthio-ADP-stimulated PLC activity. l-alpha-Threofuranosyl-UTP 13 was a P2Y receptor agonist with a preference for P2Y(2) (EC(50)=9.9 microM) versus P2Y(4) receptors. The P2Y(1) receptor binding modes, including rotational angles, were estimated using molecular modeling and receptor docking.
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