Source:http://linkedlifedata.com/resource/pubmed/id/11754592
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2001-12-28
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| pubmed:abstractText |
The potency of nucleotide antagonists at P2Y1 receptors was enhanced by replacing the ribose moiety with a constrained carbocyclic ring (Nandanan, et al. J. Med. Chem. 2000, 43, 829-842). We have now synthesized ring-constrained methanocarba analogues (in which a fused cyclopropane moiety constrains the pseudosugar ring) of adenine and uracil nucleotides, the endogenous activators of P2Y receptors. Methanocarba-adenosine 5'-triphosphate (ATP) was fixed in either a Northern (N) or a Southern (S) conformation, as defined in the pseudorotational cycle. (N)-Methanocarba-uridine was prepared from the 1-amino-pseudosugar ring by treatment with beta-ethoxyacryloyl cyanate and cyclization to form the uracil ring. Phosphorylation was carried out at the 5'-hydroxyl group through a multistep process: Reaction with phosphoramidite followed by oxidation provided the 5'-monophosphates, which then were treated with 1,1'-carbonyldiimidazole for condensation with additional phosphate groups. The ability of the analogues to stimulate phospholipase C through activation of turkey P2Y1 or human P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors stably expressed in astrocytoma cells was measured. At recombinant human P2Y1 and P2Y2 receptors, (N)-methanocarba-ATP was 138- and 41-fold, respectively, more potent than racemic (S)-methanocarba-ATP as an agonist. (N)-methanocarba-ATP activated P2Y11 receptors with a potency similar to ATP. (N)-Methanocarba-uridine 5'-triphosphate (UTP) was equipotent to UTP as an agonist at human P2Y2 receptors and also activated P2Y4 receptors with an EC(50) of 85 nM. (N)-Methanocarba-uridine 5'-diphosphate (UDP) was inactive at the hP2Y6 receptor. The vascular effects of (N)-methanocarba-UTP and (N)-methanocarba-UDP were studied in a model of the rat mesenteric artery. The triphosphate was more potent than UTP in inducing a dilatory P2Y4 response (pEC(50) = 6.1 +/- 0.2), while the diphosphate was inactive as either an agonist or antagonist in a P2Y6 receptor-mediated contractile response. Our results suggest that new nucleotide agonists may be designed on the basis of the (N) conformation that favors selectivity for P2Y1, P2Y2, P2Y4, and P2Y11 receptors.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenine Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Bicyclo Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Inositol Phosphates,
http://linkedlifedata.com/resource/pubmed/chemical/P2RY1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/P2RY11 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/P2RY2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/P2ry1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/P2ry2 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Purinergic P2 Receptor Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Purinergic P2 Receptor Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2Y1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2Y2,
http://linkedlifedata.com/resource/pubmed/chemical/Uracil Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/purinoceptor P2Y4,
http://linkedlifedata.com/resource/pubmed/chemical/purinoceptor P2Y6
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jan
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| pubmed:issn |
0022-2623
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| pubmed:author |
pubmed-author:BoyerJosé LJL,
pubmed-author:ErlingeDavidD,
pubmed-author:HardenT KendallTK,
pubmed-author:JacobsonKenneth AKA,
pubmed-author:KimHak SungHS,
pubmed-author:MaddiletiSavitriS,
pubmed-author:MalmsjöMalinM,
pubmed-author:MarquezVictor EVE,
pubmed-author:RaviR GnanaRG,
pubmed-author:WihlborgAnna-KarinAK
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| pubmed:issnType |
Print
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| pubmed:day |
3
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| pubmed:volume |
45
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
208-18
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| pubmed:dateRevised |
2011-11-17
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| pubmed:meshHeading |
pubmed-meshheading:11754592-Adenine Nucleotides,
pubmed-meshheading:11754592-Animals,
pubmed-meshheading:11754592-Bicyclo Compounds,
pubmed-meshheading:11754592-Erythrocyte Membrane,
pubmed-meshheading:11754592-Humans,
pubmed-meshheading:11754592-Inositol Phosphates,
pubmed-meshheading:11754592-Molecular Conformation,
pubmed-meshheading:11754592-Purinergic P2 Receptor Agonists,
pubmed-meshheading:11754592-Purinergic P2 Receptor Antagonists,
pubmed-meshheading:11754592-Rats,
pubmed-meshheading:11754592-Receptors, Purinergic P2,
pubmed-meshheading:11754592-Receptors, Purinergic P2Y1,
pubmed-meshheading:11754592-Receptors, Purinergic P2Y2,
pubmed-meshheading:11754592-Stereoisomerism,
pubmed-meshheading:11754592-Structure-Activity Relationship,
pubmed-meshheading:11754592-Tumor Cells, Cultured,
pubmed-meshheading:11754592-Turkey,
pubmed-meshheading:11754592-Uracil Nucleotides
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| pubmed:year |
2002
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| pubmed:articleTitle |
Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptors.
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| pubmed:affiliation |
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
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| pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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