Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system

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 modi. cation 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(3)AR agonists. Compounds 33b-39b (N-6-3-halobenzyl and related arylalkyl derivatives) were potent A(3)AR antagonists with binding K-i values of 0.7-1.4 nM. In a functional assay of [S-35] GTP gamma S 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(3)AR antagonists has been described. (C) 2008 Elsevier Ltd. All rights reserved.