ArticleJournal of medicinal chemistry2002
Adenine nucleotide analogues locked in a Northern methanocarba conformation: enhanced stability and potency as P2Y(1) receptor agonists.
Article in Journal of medicinal chemistry, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 59 citations in OpenAlex.
- MRS2339, a cardiac P2X4 receptor nucleotide activator, improves systolic function in heart failure.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- 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
- Synthesis and Effect of Conformationally Locked Carbocyclic Guanine Nucleotides on Dynamin.Biomolecules · 2022Article
- Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets.RSC medicinal chemistry · 2021Review
- Neuroprotective Roles of the Adenosine ANeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- Convergent synthesis of 2-thioether-substituted (RSC advances · 2021Article
- Medicinal chemistry of P2 and adenosine receptors: Common scaffolds adapted for multiple targets.Biochemical pharmacology · 2021Review
- Nucleotide P2YPurinergic signalling · 2020Article
- Influence of spatially segregated IPProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Prevention and rescue of cardiac dysfunction by methanocarba adenosine monophosphonate derivatives.Purinergic signalling · 2020Article
- Survey of ribose ring pucker of signaling nucleosides and nucleotides.Nucleosides, nucleotides & nucleic acids · 2020Article
- Demystifying P2YJournal of chemical information and modeling · 2017Article
- Polypharmacology of conformationally locked methanocarba nucleosides.Drug discovery today · 2017Review
- Platelet-derived growth factor receptor-α-positive cells and not smooth muscle cells mediate purinergic hyperpolarization in murine colonic muscles.American journal of physiology. Cell physiology · 2014Article
- P2Y1 receptor-mediated potentiation of inspiratory motor output in neonatal rat in vitro.The Journal of physiology · 2014Article
- Purinergic inhibitory regulation of murine detrusor muscles mediated by PDGFRα+ interstitial cells.The Journal of physiology · 2014Article
- Pharmacological characterization of the P2 receptors profile in the podocytes of the freshly isolated rat glomeruli.American journal of physiology. Cell physiology · 2013Article
- Stroke neuroprotection: targeting mitochondria.Brain sciences · 2013Article
- 5'-Phosphate and 5'-phosphonate ester derivatives of (N)-methanocarba adenosine with in vivo cardioprotective activity.Journal of medicinal chemistry · 2013Article
- P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential.CNS & neurological disorders drug targets · 2012Review
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y(1) or human P2Y(1) and P2Y(2) receptors stably expressed in astrocytoma cells. An (N)-methanocarba-2-methylthio-ADP analogue displayed an EC(50) at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N(6)-Me analogue were also highly selective, full agonists at P2Y(1) receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,gamma-methylene-ATP was inactive at P2Y receptors, beta,gamma-methylene-(N)-methanocarba-ATP was a potent hP2Y(1) receptor agonist with an EC(50) of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y(1) receptors.
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