N6-substituted D-4'-thioadenosine-5'-methyluronamides: potent and selective agonists at the human A3 adenosine receptor

J Med Chem. 2003 Aug 28;46(18):3775-7. doi: 10.1021/jm034098e.

Abstract

4'-Thio analogues 3-5 of Cl-IB-MECA (2) (K(i) = 1.0 +/- 0.2 nM at the human A(3) adenosine receptor) were synthesized from d-gulono-gamma-lactone via 4-thioribosyl acetate 14 as the key intermediate. All synthesized 4'-thionucleosides exhibited higher binding affinity to the human A(3) adenosine receptor than Cl-IB-MECA, among which 4 showed the most potent binding affinity (K(i) = 0.28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry*
  • Animals
  • CHO Cells
  • Cerebral Cortex / metabolism
  • Corpus Striatum / metabolism
  • Cricetinae
  • Humans
  • Ligands
  • Purinergic P1 Receptor Agonists*
  • Radioligand Assay
  • Rats
  • Receptor, Adenosine A3
  • Structure-Activity Relationship
  • Thionucleosides / chemical synthesis*
  • Thionucleosides / chemistry
  • Thionucleosides / pharmacology

Substances

  • Ligands
  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A3
  • Thionucleosides
  • Adenosine
  • 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide