Linked Life Data

9667972

Source:http://linkedlifedata.com/resource/pubmed/id/9667972

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
1998-8-3
pubmed:abstractText
The adenosine antagonist 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1, 5-c]quinazolin-5-amine (CGS 15943) binds nonselectively to human A1, A2A, and A3 receptors with high affinity. Acylated derivatives and one alkyl derivative of the 5-amino group and other modifications were prepared in an effort to enhance A2B or A3 subtype potency. In general, distal modifications of the N5-substituent were highly modulatory to potency and selectivity at adenosine receptors, as determined in radioligand binding assays at rat brain A1 and A2A receptors and at recombinant human A3 receptors. In Chinese hamster ovary cells stably transfected with human A2B receptor cDNA, inhibition of agonist-induced cyclic AMP production was measured. An N5-(2-iodophenyl)acetyl derivative was highly selective for A2A receptors. An (R)-N5-alpha-methyl(phenylacetyl) derivative was the most potent derivative at A3 receptors, with a Ki value of 0.36 nM. A bulky N5-diphenylacetyl derivative, 13, displayed a Ki value of 0. 59 nM at human A3 receptors and was moderately selective for that subtype. Thus, a large, nondiscriminating hydrophobic region occurs in the A3 receptor in proximity to the N5-substituent. A series of straight-chain N5-aminoalkylacyl derivatives demonstrated that for A2B receptors the optimal chain length occurs with three methylene groups, i.e., the N5-gamma-aminobutyryl derivative 27 which had a pA2 value of 8.0 but was not selective for A2B receptors. At A1, A2A, and A3 receptors however the optimum occurs with four methylene groups. An N5-pivaloyl derivative, which was less potent than 27 at A1, A2A, and A3 receptors, retained moderate potency at A2B receptors. A molecular model of the 27-A2B receptor complex based on the structure of rhodopsin utilizing a "cross-docking" procedure was developed in order to visualize the environment of the ligand binding site.
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
16
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2835-45
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:9667972-Animals, pubmed-meshheading:9667972-CHO Cells, pubmed-meshheading:9667972-Cerebral Cortex, pubmed-meshheading:9667972-Cricetinae, pubmed-meshheading:9667972-Cyclic AMP, pubmed-meshheading:9667972-Humans, pubmed-meshheading:9667972-Models, Molecular, pubmed-meshheading:9667972-Molecular Conformation, pubmed-meshheading:9667972-Protein Conformation, pubmed-meshheading:9667972-Purinergic P1 Receptor Antagonists, pubmed-meshheading:9667972-Quinazolines, pubmed-meshheading:9667972-Rats, pubmed-meshheading:9667972-Receptor, Adenosine A2A, pubmed-meshheading:9667972-Receptor, Adenosine A2B, pubmed-meshheading:9667972-Receptor, Adenosine A3, pubmed-meshheading:9667972-Receptors, Purinergic P1, pubmed-meshheading:9667972-Recombinant Proteins, pubmed-meshheading:9667972-Structure-Activity Relationship, pubmed-meshheading:9667972-Triazoles
pubmed:year
1998
pubmed:articleTitle
Derivatives of the triazoloquinazoline adenosine antagonist (CGS 15943) having high potency at the human A2B and A3 receptor subtypes.
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.
pubmed:publicationType
Journal Article