Document Detail


Nucleoside transport inhibition and platelet aggregation in human blood: R75231 and its enantiomers, draflazine and R88016.
MedLine Citation:
PMID:  8137884     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we determined whether R75231, (+/-)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis( 4-fluoro- phenyl)pentyl]-1-piperazineacetamide, and its two enantiomers, all nucleoside transport inhibitors, could play a role as anti-aggregatory agents. First, we determined the binding characteristics of [3H]nitrobenzylthioinosine, also a nucleoside transport inhibitor, on intact human erythrocytes. The Kd value was 0.27 +/- 0.04 nM and the Bmax was 23.5 +/- 5.1 pmol/10(9) erythrocytes. Second, we studied the ability of R75231 and its enantiomers R88021 ((-)-R75231, or draflazine) and R88016 ((+)-R75231), to displace [3H]nitrobenzylthioinosine. R75231 had an IC50 value of 2.2 +/- 0.3 nM. R88021 was twice as potent as R75231 and R88016 was approximately 20-fold less potent than R75231. Finally, the ability of these nucleoside transport inhibitors to enhance anti-aggregatory effects of adenosine was examined in whole human blood. Adenosine alone, 10 microM, had no effect on ADP-induced platelet aggregation. However, in the presence of 1 microM R75231, 10 microM of adenosine inhibited the aggregatory response completely. Dose-response curves indicated that the IC50 values of draflazine and R88016 were approximately 0.5 microM and 10 microM, respectively. R75231 and its enantiomers are valuable research tools to assess the role of the nucleoside transporter. Moreover, R75231 and draflazine (R88021) may prove to be useful as anti-aggregatory agents.
Authors:
M W Beukers; C J Kerkhof; A P IJzerman; W Soudijn
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  European journal of pharmacology     Volume:  266     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  1994 Jan 
Date Detail:
Created Date:  1994-04-25     Completed Date:  1994-04-25     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  57-62     Citation Subset:  IM    
Affiliation:
Division of Medicinal Chemistry, Leiden-Amsterdam Center for Drug Research, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Adenosine / pharmacology
Adenosine Diphosphate / pharmacology
Binding Sites
Biological Transport / drug effects
Blood Platelets / drug effects
Erythrocytes / drug effects*,  metabolism
Humans
Piperazines / pharmacology*
Platelet Aggregation / drug effects*
Platelet Aggregation Inhibitors / pharmacology*
Radioligand Assay
Stereoisomerism
Thioinosine / analogs & derivatives*,  blood
Chemical
Reg. No./Substance:
0/Piperazines; 0/Platelet Aggregation Inhibitors; 120770-34-5/draflazine; 38048-32-7/4-nitrobenzylthioinosine; 574-25-4/Thioinosine; 58-61-7/Adenosine; 58-64-0/Adenosine Diphosphate

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