Selective A 3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system

Abstract

We have prepared 5′-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0]hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A 3 AR. The H-bonding ability of a group of 9-riboside derivatives containing a 5′-uronamide moiety was reduced by modification of the NH; however these derivatives did not display the desired activity as selective A 3 AR antagonists, as occurs with 5′- N, N-dimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 4′-hydroxymethyl group were highly potent and selective antagonists of the human A 3 AR. The compounds were synthesized from d-ribose using a reductive free radical decarboxylation of a 5′-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A 3AR agonists. Compounds 33b– 39b ( N 6-3-halobenzyl and related arylalkyl derivatives) were potent A 3AR antagonists with binding K i values of 0.7–1.4 nM. In a functional assay of [ 35S]GTPγS binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a K B of 8.9 nM. Thus, a highly potent and selective series of A 3AR antagonists has been described.