Source:http://linkedlifedata.com/resource/pubmed/id/10479295
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
18
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pubmed:dateCreated |
1999-10-14
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pubmed:abstractText |
P2-Receptors (P2-Rs) represent significant targets for novel drug development. P2-Rs were identified also on pancreatic B cells and are involved in insulin secretion. Therefore, novel P2Y-R ligands, 2-thioether 5'-O-phosphorothioate adenosine derivatives (2-RS-ATP-alpha-S), were synthesized as potential insulin secretagogues. An efficient synthesis of these nucleotides and a facile method for separation of the chiral products are described. The enzymatic stability of the compounds toward pig pancreas type I ATPDase was evaluated. The rate of hydrolysis of 2-hexylthio-5'-O-(1-thiotriphosphate)adenosine (2-hexylthio-ATP-alpha-S) isomers by ATPDase was 28% of that of ATP. Some 2-thioether 5'-(monophosphorothioate)adenosine derivatives (2-RS-AMP-S) exerted an inhibitory effect on ATPDase. The apparent affinity of the compounds to P2Y(1)-R was determined by measurement of P2Y-R-promoted phospholipase C activity in turkey erythrocyte membranes. 2-RS-ATP-alpha-S derivatives were agonists, stimulating the production of inositol phosphates with K(0.5) values in the nanomolar range. 2-RS-AMP-S derivatives were full agonists, although 2 orders of magnitude less potent. All the compounds were more potent than ATP. The effect on insulin secretion and pancreatic flow rate was evaluated on isolated and perfused rat pancreas. A high increase, up to 500%, in glucose-induced insulin secretion was due to addition of 2-hexylthio-ATP-alpha-S in the nanomolar concentration range, which represents 100-fold enhancement of activity relative to ATP. 2-Hexylthio-AMP-S was 2.5 orders of magnitude less effective.
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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/Adenosine,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Apyrase,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Purinergic P2 Receptor Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfides,
http://linkedlifedata.com/resource/pubmed/chemical/Thionucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/adenosine 5'-(1-thio)triphosphate
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
42
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3636-46
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:10479295-Adenosine,
pubmed-meshheading:10479295-Adenosine Triphosphate,
pubmed-meshheading:10479295-Animals,
pubmed-meshheading:10479295-Apyrase,
pubmed-meshheading:10479295-Enzyme Stability,
pubmed-meshheading:10479295-Insulin,
pubmed-meshheading:10479295-Islets of Langerhans,
pubmed-meshheading:10479295-Kinetics,
pubmed-meshheading:10479295-Nucleotides,
pubmed-meshheading:10479295-Pancreas,
pubmed-meshheading:10479295-Purinergic P2 Receptor Agonists,
pubmed-meshheading:10479295-Sulfides,
pubmed-meshheading:10479295-Swine,
pubmed-meshheading:10479295-Thionucleotides
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pubmed:year |
1999
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pubmed:articleTitle |
2-thioether 5'-O-(1-thiotriphosphate)adenosine derivatives as new insulin secretagogues acting through P2Y-Receptors.
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pubmed:affiliation |
Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel. bfischer@mail.biu.ac.il
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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