Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / analogs & derivatives*
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Adenosine / chemical synthesis
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Adenosine / metabolism
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Adenosine / therapeutic use
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Adenosine A1 Receptor Agonists*
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Adenosine A2 Receptor Agonists
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Adenosine A3 Receptor Agonists*
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Animals
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CHO Cells
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Cardiotonic Agents / chemical synthesis*
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Cricetinae
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Drug Design
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Humans
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Mice
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Myocardial Infarction / prevention & control
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Receptor, Adenosine A1 / metabolism
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Receptor, Adenosine A2A / metabolism
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Receptor, Adenosine A3 / metabolism
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Reperfusion Injury / prevention & control
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Ventricular Function, Left / drug effects
Substances
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Adenosine A1 Receptor Agonists
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Adenosine A2 Receptor Agonists
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Adenosine A3 Receptor Agonists
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Cardiotonic Agents
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Receptor, Adenosine A1
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Receptor, Adenosine A2A
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Receptor, Adenosine A3
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Adenosine