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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
16
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pubmed:dateCreated |
1997-9-10
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pubmed:abstractText |
4-(Phenylethynyl)-6-phenyl-1,4-dihydropyridine derivatives are selective antagonists at human A3 adenosine receptors, with Ki values in a radioligand binding assay vs [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5'-(N-methylcarbamoyl)adenosine) in the submicromolar range. In this study, structure-activity relationships at various positions of the dihydropyridine ring (the 3- and 5-acyl substituents, the 4-aryl substituent, and 1-methyl group) were probed synthetically. Using the combined protection of the 1-ethoxymethyl and the 5-[2-(trimethylsilyl)ethyl] ester groups, a free carboxylic acid was formed at the 5-position allowing various substitutions. Selectivity of the new analogues for cloned human A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A2A receptors. Structure-activity analysis at adenosine receptors indicated that pyridyl, furyl, benzofuryl, and thienyl groups at the 4-position resulted in, at most, only moderate selectivity for A3 adenosine receptors. Ring substitution (e.g., 4-nitro) of the 4-phenylethylnyl group did not provide enhanced selectivity, as it did for the 4-styryl-substituted dihydropyridines. At the 3-position of the dihydropyridine ring, esters were much more selective for A3 receptors than closely related thioester, amide, and ketone derivatives. A cyclic 3-keto derivative was 5-fold more potent at A3 receptors than a related open-ring analogue. At the 5-position, a homologous series of phenylalkyl esters and a series of substituted benzyl esters were prepared and tested. (Trifluoromethyl)-, nitro-, and other benzyl esters substituted with electron-withdrawing groups were specific for A3 receptors with nanomolar Ki values and selectivity as high as 37000-fold. A functionalized congener bearing an [(aminoethyl)amino]carbonyl group was also prepared as an intermediate in the synthesis of biologically active conjugates.
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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/Affinity Labels,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channel Blockers,
http://linkedlifedata.com/resource/pubmed/chemical/Dihydropyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Iodine Radioisotopes,
http://linkedlifedata.com/resource/pubmed/chemical/MRS 1097,
http://linkedlifedata.com/resource/pubmed/chemical/N(6)-(4-amino-3-iodobenzyl)adenosine...,
http://linkedlifedata.com/resource/pubmed/chemical/Purinergic P1 Receptor Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Adenosine A3
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
40
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2596-608
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:9258367-Adenosine,
pubmed-meshheading:9258367-Affinity Labels,
pubmed-meshheading:9258367-Animals,
pubmed-meshheading:9258367-CHO Cells,
pubmed-meshheading:9258367-Calcium Channel Blockers,
pubmed-meshheading:9258367-Cerebral Cortex,
pubmed-meshheading:9258367-Cricetinae,
pubmed-meshheading:9258367-Dihydropyridines,
pubmed-meshheading:9258367-Humans,
pubmed-meshheading:9258367-Iodine Radioisotopes,
pubmed-meshheading:9258367-Kinetics,
pubmed-meshheading:9258367-Models, Chemical,
pubmed-meshheading:9258367-Purinergic P1 Receptor Antagonists,
pubmed-meshheading:9258367-Rats,
pubmed-meshheading:9258367-Receptor, Adenosine A3,
pubmed-meshheading:9258367-Structure-Activity Relationship
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pubmed:year |
1997
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pubmed:articleTitle |
Structure-activity relationships of 4-(phenylethynyl)-6-phenyl-1,4-dihydropyridines as highly selective A3 adenosine receptor antagonists.
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pubmed:affiliation |
Molecular Recognition Section, 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,
Research Support, Non-U.S. Gov't
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