Dual acting antioxidant A1 adenosine receptor agonists.
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.
Gregg
Alison
A
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia.
Bottle
Steven E
SE
Devine
Shane M
SM
Figler
Heidi
H
Linden
Joel
J
White
Paul
P
Pouton
Colin W
CW
Urmaliya
Vijay
V
Scammells
Peter J
PJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D007202:Indicators and Reagents; D054833:Isoindoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D000975:Antioxidants; D002316:Cardiotonic Agents; D007202:Indicators and Reagents; D054833:Isoindoles; C524327:N(6)-(2,2,5,5-tetramethylpyrrolidin-1-yloxyl-3-ylmethyl)adenosine; C524328:N(6)-(4-(2-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-amido)ethyl)phenyl)adenosine; D011759:Pyrrolidines; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine