Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists

Adenosine receptor agonists have cardioprotective, cerebroprotective, and a ntiinflammatory properties. We report that a carbocyclic modification of th e ribose moiety incorporating ring constraints is a general approach for th e design of A(1) and A(3) receptor agonists having favorable pharmacodynami c properties. While simple carbocyclic substitution of adenosine agonists g reatly diminishes potency, methanocarba-adenosine analogues have now define d the role of sugar puckering in stabilizing the active adenosine receptor- bound conformation and thereby have allowed identification of a favored iso mer. In such analogues a fused cyclopropane moiety constrains the pseudosug ar ring of the nucleoside to either a Northern (N) or Southern (S) conforma tion, as defined in the pseudorotational cycle. In binding assays at A(1), A(2A), and A(3) receptors, (N)-methanocarba-adenosine was of higher affinit y than the (S)-analogue, particularly at the human A(3) receptor (N/S affin ity ratio of 150). (N)-Methanocarba analogues of various N-6-substituted ad enosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the p arent compounds are potent agonists at either A(1) or A(3) receptors, respe ctively, were synthesized. The N-6-cyclopentyl derivatives were A(1) recept or-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding of [S-35] GTP- gamma-S. The (N)-methanocarba-N-6-(3-iodobenzyl)adenosine and its 2-chloro derivative had K-i values of 4.1 and 2.2 nM at A(3) receptors, respectively , and were highly selective partial agonists. Partial agonism combined with high functional potency at A(3) receptors (EC50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y(1) receptors, at least three adenos ine receptors favor the ribose (N)-conformation.