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)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.
Jacobson
Kenneth A
KA
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. kajacobs@helix.nih.gov
Gao
Zhan-Guo
ZG
Tchilibon
Susanna
S
Duong
Heng T
HT
Joshi
Bhalchandra V
BV
Sonin
Dmitry
D
Liang
Bruce T
BT
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D002316:Cardiotonic Agents / Q000138:chemical synthesis*; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction / Q000517:prevention & control; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D002316:Cardiotonic Agents; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D000241:Adenosine