Selective A3 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,Ndimethyluronamides. 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 [ 35 S]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 3 AR antagonists has been described.

Extended N6 substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor

“…8 The corresponding 4′-truncated (N)-methanocarba nucleoside containing a racemic N 6 -(2-phenylcyclopropyl) substitution was found to be a selective A 3 AR antagonist (K i 1.3 nM). 13 The 1 S,2R diastereoisomer of 2 was ~10-fold more potent in binding to the hA 3 AR (K i 11.2 nM) than the corresponding 1 R ,2 S isomer. This N 6 substituent was also combined with C2-cyano or carboxamide substitution in a subsequent 9-riboside series resulting in a moderate reduction of A 3 AR affinity.…”

Synthesis and evaluation of N6-substituted apioadenosines as potential adenosine A3 receptor modulators

“…behaving as partial agonist or antagonist of this subtype. [24] Our docking of nucleoside analogues in the hA 3 AR homology model indicated that the absence of a hydroxymethyl or uronamide substituent at the 4′-position prevented these compounds from interacting with Thr94 (3.36). This residue is a conserved recognition point in agonist binding, and therefore the lack of this interaction was considered as a reason for the low efficacy profile of 4′-truncated nucleosides.…”

“…[24] Binding and functional parameters were calculated using Prism 5.0 software (GraphPAD, San Diego, CA, USA). IC 50 values obtained from competition curves were converted to K i values using the Cheng-Prusoff equation.…”

Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches

“…The truncated (N)-methanocarba purine analogues 99 (MRS5474) and 100 (MRS5719) showed selectivity as A 1 AR full agonist and partial agonist, respectively. 20 The 2-phenylalkynyl derivative 21 in the truncated series showed selectivity as an A 3 AR antagonist, 19,21 and the related 5′-methyluronamides 101 (MRS5697) and 102 (MRS5698) were highly selective agonists at both human and mouse A 3 ARs. 18 …”

“…21 Extensive modification of this class of molecules provided various lead molecules to achieve selectivity for either the A 1 AR or the A 3 AR. 19,20 The cyclopentone derivative 22b was synthesized from D-ribose 22a in six steps (Scheme 3c), 22 a and the glycosyl sugar 22c was formed upon the stereoselective reduction of 22b by sodium borohydride in the presence of cerium(III) chloride followed by a Simmons–Smith cyclopropanation of the resulting alcohol.…”