Abstract
Herein we report the synthesis and biological evaluation of some potent and selective A(1) adenosine receptor agonists, which incorporate a functionalised linker attached to an antioxidant moiety. N(6)-(2,2,5,5-Tetramethylpyrrolidin-1-yloxyl-3-ylmethyl)adenosine (VCP28, 2e) proved to be an agonist with high affinity (K(i)=50nM) and good selectivity (A(3)/A(1) > or = 400) for the A(1) adenosine receptor. N(6)-[4-[2-[1,1,3,3-Tetramethylisoindolin-2-yloxyl-5-amido]ethyl]phenyl]adenosine (VCP102, 5a) has higher binding affinity (K(i)=7 nM), but lower selectivity (A(3)/A(1)= approximately 3). All compounds bind weakly (K(i)>1 microM) to A(2A) and A(2B) receptors. The combination of A(1) agonist activity and antioxidant activity has the potential to produce cardioprotective effects.
Publication types
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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 / pharmacology
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Adenosine A1 Receptor Agonists*
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Animals
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Antioxidants / chemical synthesis*
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Antioxidants / pharmacology*
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Binding Sites
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Cardiotonic Agents / chemical synthesis
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Cardiotonic Agents / pharmacology
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Cell Line
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Indicators and Reagents
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Isoindoles / chemical synthesis*
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Isoindoles / pharmacology*
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Myocardial Ischemia / drug therapy
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Myocardial Ischemia / pathology
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Myocardial Reperfusion Injury / drug therapy
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Myocardial Reperfusion Injury / pathology
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Myocytes, Cardiac / drug effects
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacology*
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Rats
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Structure-Activity Relationship
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Xanthines / pharmacology
Substances
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Adenosine A1 Receptor Agonists
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Antioxidants
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Cardiotonic Agents
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Indicators and Reagents
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Isoindoles
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N(6)-(2,2,5,5-tetramethylpyrrolidin-1-yloxyl-3-ylmethyl)adenosine
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N(6)-(4-(2-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-amido)ethyl)phenyl)adenosine
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Pyrrolidines
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Xanthines
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1,3-dipropyl-8-cyclopentylxanthine
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Adenosine