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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2010-5-10
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pubmed:abstractText |
Multivalent dendrimeric conjugates of GPCR ligands may have increased potency or selectivity in comparison to monomeric ligands, a phenomenon that was tested in a model of cytoprotection in mouse HL-1 cardiomyocytes. Quantitative RT-PCR indicated high expression levels of endogenous A(1) and A(2A) adenosine receptors (ARs), but not of A(2B) and A(3)ARs. Activation of the heterologously expressed human A(3)AR in HL-1 cells by AR agonists significantly attenuated cell damage following 4h exposure to H(2)O(2) (750 microM) but not in untransfected cells. The A(3) agonist IB-MECA (EC(50) 3.8 microM) and the non-selective agonist NECA (EC(50) 3.9 microM) protected A(3) AR-transfected cells against H(2)O(2) in a concentration-dependent manner, as determined by lactate dehydrogenase release. A generation 5.5 PAMAM (polyamidoamine) dendrimeric conjugate of a N(6)-chain-functionalized adenosine agonist was synthesized and its mass indicated an average of 60 amide-linked nucleoside moieties out of 256 theoretical attachment sites. It non-selectively activated the A(3)AR to inhibit forskolin-stimulated cAMP formation (IC(50) 66nM) and, similarly, protected A(3)-transfected HL-1 cells from apoptosis-inducing H(2)O(2) with greater potency (IC(50) 35nM) than monomeric nucleosides. Thus, a PAMAM conjugate retained AR binding affinity and displayed greatly enhanced cardioprotective potency.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20346920-10449539,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20346920-9501201
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1873-2968
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pubmed:author |
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pubmed:copyrightInfo |
Published by Elsevier Inc.
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
80
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
188-96
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pubmed:dateRevised |
2011-9-29
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pubmed:meshHeading |
pubmed-meshheading:20346920-Adenosine,
pubmed-meshheading:20346920-Adenosine-5'-(N-ethylcarboxamide),
pubmed-meshheading:20346920-Animals,
pubmed-meshheading:20346920-CHO Cells,
pubmed-meshheading:20346920-Cell Death,
pubmed-meshheading:20346920-Cells, Cultured,
pubmed-meshheading:20346920-Cricetinae,
pubmed-meshheading:20346920-Cricetulus,
pubmed-meshheading:20346920-Cytoprotection,
pubmed-meshheading:20346920-Dendrimers,
pubmed-meshheading:20346920-Gene Expression Regulation,
pubmed-meshheading:20346920-Humans,
pubmed-meshheading:20346920-Hydrogen Peroxide,
pubmed-meshheading:20346920-Mice,
pubmed-meshheading:20346920-Myocytes, Cardiac,
pubmed-meshheading:20346920-Oxidants,
pubmed-meshheading:20346920-Protein Binding,
pubmed-meshheading:20346920-Receptors, Purinergic P1,
pubmed-meshheading:20346920-Transfection
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pubmed:year |
2010
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pubmed:articleTitle |
Multivalent dendrimeric and monomeric adenosine agonists attenuate cell death in HL-1 mouse cardiomyocytes expressing the A(3) receptor.
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pubmed:affiliation |
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
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