Design, synthesis, and binding of homologated truncated 4'-thioadenosine derivatives at the human A3 adenosine receptors

Bioorg Med Chem. 2010 Oct 1;18(19):7015-21. doi: 10.1016/j.bmc.2010.08.018. Epub 2010 Aug 14.

Abstract

We synthesized homologated truncated 4'-thioadenosine analogues 3 in which a methylene (CH(2)) group was inserted in place of the glycosidic bond of a potent and selective A(3) adenosine receptor antagonist 2. The analogues were designed to induce maximum binding interaction in the binding site of the A(3) adenosine receptor. However, all homologated nucleosides were devoid of binding affinity at all subtypes of adenosine receptors, indicating that free rotation through the single bond allowed the compound to adopt an indefinite number of conformations, disrupting the favorable binding interaction essential for receptor recognition.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Adenosine A3 Receptor Antagonists / chemical synthesis*
  • Adenosine A3 Receptor Antagonists / chemistry
  • Adenosine A3 Receptor Antagonists / pharmacology*
  • Binding Sites
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Receptor, Adenosine A3 / chemistry
  • Receptor, Adenosine A3 / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thionucleosides / chemical synthesis*
  • Thionucleosides / chemistry
  • Thionucleosides / pharmacology*

Substances

  • Adenosine A3 Receptor Antagonists
  • Receptor, Adenosine A3
  • Thionucleosides
  • 4'-thioadenosine
  • Adenosine