Linked Life Data

12919933

Source:http://linkedlifedata.com/resource/pubmed/id/12919933

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2003-11-17
pubmed:abstractText
We recently reported the identification of a novel human adenosine A3 receptor-selective agonist, (2S,3S,4R,5R)-3-amino-5-[6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylamino]purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-608,039), with 1,260-fold selectivity for the human A3 versus human A1 receptor (DeNinno et al., J Med Chem 46: 353-355, 2003). However, because the modest (20-fold) rabbit A3 receptor selectivity of CP-608,039 precludes demonstration of A3-mediated cardioprotection in rabbit models, we identified another member of this class, (2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903), which both retained human A3 receptor selectivity (210-fold; human A3/human A1 Ki: 23/4,800 nM) and had improved rabbit A3 receptor selectivity (90-fold; rabbit A3/rabbit A1 Ki: 23/2,000 nM). Infarct size was measured in Langendorff hearts or in vivo after 30 min of regional ischemia and 120 min of reperfusion. Five-minute perfusion with CP-532,903 before ischemia-reperfusion elicited a concentration-dependent reduction in infarct size in isolated hearts (EC50: 0.97 nM; maximum reduction in infarct size: 77%, P < 0.05 vs. control). Furthermore, administration of CP-532,903 (150 nM) at reperfusion also significantly reduced infarct size by 64% (P < 0.05 vs. control), which was not different (P > or = 0.05) from the cardioprotection provided by the same concentration of drug given before ischemia. The selective rabbit A1 receptor antagonist BWA1433 did not affect CP-532,903-dependent cardioprotection. In vivo, CP-532,903 (1 mg/kg) reduced infarct size by 50% in the absence of significant hemodynamic effects (mean arterial pressure, heart rate, rate-pressure product). CP-532,903 and CP-608,039 represent a novel class of human A3 receptor-selective agonists that may prove suitable for investigation of the clinical cardioprotective efficacy of A3 receptor activation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0363-6135
pubmed:author
pubmed:issnType
Print
pubmed:volume
285
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
H2780-7
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:12919933-Adenosine, pubmed-meshheading:12919933-Adenosine A3 Receptor Agonists, pubmed-meshheading:12919933-Animals, pubmed-meshheading:12919933-CHO Cells, pubmed-meshheading:12919933-Cricetinae, pubmed-meshheading:12919933-Disease Models, Animal, pubmed-meshheading:12919933-Dose-Response Relationship, Drug, pubmed-meshheading:12919933-Furans, pubmed-meshheading:12919933-Humans, pubmed-meshheading:12919933-Iodine Radioisotopes, pubmed-meshheading:12919933-Isoxazoles, pubmed-meshheading:12919933-Myocardial Infarction, pubmed-meshheading:12919933-Myocardial Reperfusion Injury, pubmed-meshheading:12919933-Purines, pubmed-meshheading:12919933-Rabbits, pubmed-meshheading:12919933-Radioligand Assay, pubmed-meshheading:12919933-Receptor, Adenosine A3, pubmed-meshheading:12919933-Sertraline, pubmed-meshheading:12919933-Transfection
pubmed:year
2003
pubmed:articleTitle
Novel N6-substituted adenosine 5'-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury.
pubmed:affiliation
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, MS8220-3125, Eastern Point Rd., Groton, CT 06340, USA. w_ross_tracey@groton.pfizer.com
pubmed:publicationType
Journal Article