pubmed-article:11754592 | rdf:type | pubmed:Citation | lld:pubmed |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C0001413 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C0041917 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1418219 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1418217 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1418218 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1418220 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C0390418 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C0026377 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C0392747 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1260969 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1554963 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1709269 | lld:lifeskim |
pubmed-article:11754592 | lifeskim:mentions | umls-concept:C1656349 | lld:lifeskim |
pubmed-article:11754592 | pubmed:issue | 1 | lld:pubmed |
pubmed-article:11754592 | pubmed:dateCreated | 2001-12-28 | lld:pubmed |
pubmed-article:11754592 | 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. | lld:pubmed |
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pubmed-article:11754592 | pubmed:language | eng | lld:pubmed |
pubmed-article:11754592 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
pubmed-article:11754592 | pubmed:citationSubset | IM | lld:pubmed |
pubmed-article:11754592 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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pubmed-article:11754592 | pubmed:status | MEDLINE | lld:pubmed |
pubmed-article:11754592 | pubmed:month | Jan | lld:pubmed |
pubmed-article:11754592 | pubmed:issn | 0022-2623 | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:MarquezVictor... | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:HardenT... | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:KimHak SungHS | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:RaviR GnanaRG | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:MaddiletiSavi... | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:WihlborgAnna-... | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:ErlingeDavidD | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:MalmsjöMalinM | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:BoyerJosé LJL | lld:pubmed |
pubmed-article:11754592 | pubmed:author | pubmed-author:JacobsonKenne... | lld:pubmed |
pubmed-article:11754592 | pubmed:issnType | Print | lld:pubmed |
pubmed-article:11754592 | pubmed:day | 3 | lld:pubmed |
pubmed-article:11754592 | pubmed:volume | 45 | lld:pubmed |
pubmed-article:11754592 | pubmed:owner | NLM | lld:pubmed |
pubmed-article:11754592 | pubmed:authorsComplete | Y | lld:pubmed |
pubmed-article:11754592 | pubmed:pagination | 208-18 | lld:pubmed |
pubmed-article:11754592 | pubmed:dateRevised | 2011-11-17 | lld:pubmed |
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pubmed-article:11754592 | pubmed:year | 2002 | lld:pubmed |
pubmed-article:11754592 | 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. | lld:pubmed |
pubmed-article:11754592 | 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. | lld:pubmed |
pubmed-article:11754592 | pubmed:publicationType | Journal Article | lld:pubmed |
pubmed-article:11754592 | pubmed:publicationType | In Vitro | lld:pubmed |
pubmed-article:11754592 | pubmed:publicationType | Research Support, U.S. Gov't, P.H.S. | lld:pubmed |
pubmed-article:11754592 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
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