Semi-rational design of (north)-methanocarba nucleosides as dual acting A(1) and A(3) adenosine receptor agonists: novel prototypes for cardioprotection

Ring-constrained adenosine analogues have been designed to act as dual agonists at tissue-protective A(1) and A(3) adenosine receptors (ARs). 9-Ribosides transformed into the ring-constrained (N)-methanocarba-2-chloro-5'-uronamides consistently lost affinity at A(1)/A(2A)ARs and gained at A(3)A...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-12, Vol.48 (26), p.8103-8107
Main Authors: Jacobson, Kenneth A, Gao, Zhan-Guo, Tchilibon, Susanna, Duong, Heng T, Joshi, Bhalchandra V, Sonin, Dmitry, Liang, Bruce T
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - chemical synthesis
Adenosine - metabolism
Adenosine - therapeutic use
Adenosine A1 Receptor Agonists
Adenosine A2 Receptor Agonists
Adenosine A3 Receptor Agonists
Animals
Cardiotonic Agents - chemical synthesis
CHO Cells
Cricetinae
Drug Design
Humans
Mice
Myocardial Infarction - prevention & control
Receptor, Adenosine A1 - metabolism
Receptor, Adenosine A2A - metabolism
Receptor, Adenosine A3 - metabolism
Reperfusion Injury - prevention & control
Ventricular Function, Left - drug effects
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Summary:Ring-constrained adenosine analogues have been designed to act as dual agonists at tissue-protective A(1) and A(3) adenosine receptors (ARs). 9-Ribosides transformed into the ring-constrained (N)-methanocarba-2-chloro-5'-uronamides consistently lost affinity at A(1)/A(2A)ARs and gained at A(3)AR. Among 9-riboside derivatives, only N(6)-cyclopentyl and 7-norbornyl moieties were extrapolated for mixed A(1)/A(3) selectivity and rat/human A(3)AR equipotency. Consequently, 2 was balanced in affinity and potency at A(1)/A(3)ARs as envisioned and dramatically protected in an intact heart model of global ischemia and reperfusion.
ISSN:0022-2623
1520-4804