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Semi-rational design of (north)-methanocarba nucleosides as dual acting A(1) and A(3) adenosine receptor agonists: novel prototypes for cardioprotection.

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.

SUBMITTER: Jacobson KA

PROVIDER: S-EPMC2597460 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Semi-rational design of (north)-methanocarba nucleosides as dual acting A(1) and A(3) adenosine receptor agonists: novel prototypes for cardioprotection.

Jacobson Kenneth A KA Gao Zhan-Guo ZG Tchilibon Susanna S Duong Heng T HT Joshi Bhalchandra V BV Sonin Dmitry D Liang Bruce T BT

Journal of medicinal chemistry 20051201 26

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 ...[more]

PMID: 16366590

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