Dual acting antioxidant A1 adenosine receptor agonists

Herein we report the synthesis and biological evaluation of some potent and selective A, 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 = 50 nM) and good selectivity (A(3)/A(1) >= 400) for the A, adenosine receptor. N-6-[4-[2-[1,1,3,3-Tetramethylisoindolin-2-yloxyl-5-amido]ethyl]phenyl]adenosine (VCP102, 5a) has higher binding affinity (Ki = 7 nM), but lower selectivity (A(3)/A(1) = similar to 3). All compounds bind weakly (K-i > 1 mu M) to A(2A) and A(2B) receptors. The combination of-A, agonist activity and antioxidant activity has the potential to produce cardioprotective effects. (C) 2007 Elsevier Ltd. All rights reserved.