Linked Life Data

8709132

Source:http://linkedlifedata.com/resource/pubmed/id/8709132

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
1996-9-6
pubmed:abstractText
1,4-Dihydropyridine and pyridine derivatives bound to three subtypes of adenosine receptors in the micromolar range. Affinity was determined in radioligand binding assays at rat brain A1 and A2A receptors using [3H]-(R)-PIA [[3H]-(R)-N6-(phenylisopropyl)adenosine] and [3H]CGS 21680 [[3H]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]-5'-(N-ethylcarbamoyl++ +) adenosine], respectively. Affinity was determined at cloned human and rat A3 receptors using [125I]AB-MECA [N6-(4-amino-3-iodobenzyl)-5'-(N-methylcarbamoyl)adenosine]. Structure-activity analysis at adenosine receptors indicated that sterically bulky groups at the 4-, 5-, and 6-positions are tolerated. (R,S)-Nicardipine, 12, displayed Ki values of 19.6 and 63.8 microM at rat A1 and A2A receptors, respectively, and 3.25 microM at human A3 receptors. Similarly, (R)-niguldipine, 14, displayed Ki values of 41.3 and 1.90 microM at A1 and A3 receptors, respectively, and was inactive at A2A receptors. A preference for the R- vs the S-enantiomer was observed for several dihydropyridines at adenosine receptors, in contrast with the selectivity at L-type Ca2+ channels. A 4-trans-beta-styryl derivative, 24, with a Ki value of 0.670 microM at A3 receptors, was 24-fold selective vs A1 receptors (Ki = 16.1 microM) and 74-fold vs A2A receptors (Ki = 49.3 microM). The affinity of 24 at L-type Ca2+ channels, measured in rat brain membranes using [3H]isradipine, indicated a Ki value of 0.694 microM, and the compound is thus nonselective between A3 receptors and L-type Ca2+ channels. Inclusion of a 6-phenyl group enhanced A3 receptor selectivity: Compound 28 (MRS1097; 3,5-diethyl 2-methyl-6-phenyl-4-(trans-2-phenylvinyl)-1,4(R,S)-dihydro-pyridin e-3, 5-dicarboxylate) was 55-fold selective vs A1 receptors, 44-fold selective vs A2A receptors, and over 1000-fold selective vs L-type Ca2+ channels. In addition, compound 28 attenuated the A3 agonist-elicited inhibitory effect on adenylyl cyclase. Furthermore, whereas nicardipine, 12, displaced radioligand from the Na(+)-independent adenosine transporter with an apparent affinity of 5.36 +/- 1.51 microM, compound 28 displaced less than 10% of total binding at a concentration of 100 microM. Pyridine derivatives, when bearing a 4-alkyl but not a 4-phenyl group, maintained affinity for adenosine receptors. These findings indicate that the dihydropyridines may provide leads for the development of novel, selective A3 adenosine antagonists.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
19
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2980-9
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:8709132-Adenylate Cyclase, pubmed-meshheading:8709132-Animals, pubmed-meshheading:8709132-CHO Cells, pubmed-meshheading:8709132-Calcium Channel Blockers, pubmed-meshheading:8709132-Calcium Channels, pubmed-meshheading:8709132-Cell Membrane, pubmed-meshheading:8709132-Cerebral Cortex, pubmed-meshheading:8709132-Cricetinae, pubmed-meshheading:8709132-Dihydropyridines, pubmed-meshheading:8709132-Enzyme Inhibitors, pubmed-meshheading:8709132-Guinea Pigs, pubmed-meshheading:8709132-Humans, pubmed-meshheading:8709132-Isradipine, pubmed-meshheading:8709132-Molecular Structure, pubmed-meshheading:8709132-Purinergic P1 Receptor Antagonists, pubmed-meshheading:8709132-Pyridines, pubmed-meshheading:8709132-Rats, pubmed-meshheading:8709132-Receptors, Purinergic P1, pubmed-meshheading:8709132-Recombinant Proteins, pubmed-meshheading:8709132-Stereoisomerism, pubmed-meshheading:8709132-Structure-Activity Relationship
pubmed:year
1996
pubmed:articleTitle
Interaction of 1,4-dihydropyridine and pyridine derivatives with adenosine receptors: selectivity for A3 receptors.
pubmed:affiliation
Molecular Recognition Section, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't