Selective A(3) Adenosine Receptor Antagonists Derived From Nucleosides Containing a bicyclo[3.1.0]hexane Ring System

Bioorg Med Chem. 2008 Sep 15;16(18):8546-56. doi: 10.1016/j.bmc.2008.08.007. Epub 2008 Aug 7.

Abstract

We have prepared 50-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 A3 AR. The H-bonding ability of a group of 9-riboside derivatives containing a 50-uronamide moiety was reduced by modification of the NH; however these derivatives did not display the desired activity as selective A3 AR antagonists, as occurs with 50-N,N-dimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 40-hydroxymethyl group were highly potent and selective antagonists of the human A3 AR. The compounds were synthesized from D-ribose using a reductive free radical decarboxylation of a 50-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A3AR agonists. Compounds 33b-39b (N6-3-halobenzyl and related arylalkyl derivatives) were potent A3AR antagonists with binding Ki values of 0.7-1.4 nM. In a functional assay of [35S]GTPcS binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a KB of 8.9 nM. Thus, a highly potent and selective series of A3AR antagonists has been described.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine A3 Receptor Antagonists*
  • Algorithms
  • Animals
  • Binding Sites
  • Bridged Bicyclo Compounds / chemistry*
  • CHO Cells / metabolism
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Guanosine Triphosphate / metabolism
  • Humans
  • Models, Molecular
  • Nucleosides / chemical synthesis
  • Nucleosides / pharmacology*
  • Radioligand Assay
  • Receptor, Adenosine A3 / metabolism
  • Ribose / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adenosine A3 Receptor Antagonists
  • Bridged Bicyclo Compounds
  • Nucleosides
  • Receptor, Adenosine A3
  • bicyclo(3.1.0)hexane
  • Ribose
  • Guanosine Triphosphate
  • Cyclic AMP