ArticleJournal of medicinal chemistry2003
2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonists.
Article in Journal of medicinal chemistry, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 127 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
- Drug-like Antagonists of P2Y Receptor Subtypes: An Update.Journal of medicinal chemistry · 2025Review
- Design and Pharmacological Characterization of a Novel Antithrombotic P2YInternational journal of molecular sciences · 2025Article
- Pharmacological characterization of P2Y receptor subtypes - an update.Purinergic signalling · 2024Review
- Exploring bias in platelet P2YBritish journal of pharmacology · 2024Review
- One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates.Organic letters · 2023Article
- Pharmacological Profile of the Purinergic P2Y Receptors That Modulate, in Response to ADPβS, the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Targeting the P2YAmerican journal of respiratory and critical care medicine · 2022Article
- Recommended tool compounds and drugs for blocking P2X and P2Y receptors.Purinergic signalling · 2021Review
- Purinergic Receptors Crosstalk with CCR5 to Amplify CaCellular and molecular neurobiology · 2021Article
- Medicinal chemistry of P2 and adenosine receptors: Common scaffolds adapted for multiple targets.Biochemical pharmacology · 2021Review
- Burnstock and the legacy of the inhibitory junction potential and P2Y1 receptors.Purinergic signalling · 2021Review
- Astrocytes Modulate Baroreflex Sensitivity at the Level of the Nucleus of the Solitary Tract.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- The role of purinergic P2YPurinergic signalling · 2020Article
- Synthesis of bicyclo[3.1.0]hexanes by (3 + 2) annulation of cyclopropenes with aminocyclopropanes.Chemical science · 2019Article
- P2YPurinergic signalling · 2018Article
- A Component Formula of Chinese Medicine for Hypercholesterolemia Based on Virtual Screening and Biology Network.Evidence-based complementary and alternative medicine : eCAM · 2018Article
- Demystifying P2YJournal of chemical information and modeling · 2017Article
- Identification of a Different Agonist-Binding Site and Activation Mechanism of the Human P2YScientific reports · 2017Article
- Ligand binding to a G protein-coupled receptor captured in a mass spectrometer.Science advances · 2017Article
4 more citing papers are in PubMed but not listed here.
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10 authors at 1 institution in 1 country.
Funding
Abstract
Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of P2Y(1) receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829-842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y(1) receptor and by using the radiolabeled antagonist [(3)H]2-chloro-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y(1) receptor was an (N)-methanocarba N(6)-methyl-2-iodo analogue 12, which displayed a K(i) value in competition for binding of [(3)H]5 of 0.79 nM and a K(B) value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y(1) receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(1-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y(1) receptors. An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored.
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