Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5'-ribofuran-uronamide moiety

Bioorg Med Chem Lett. 2006 Feb;16(3):596-601. doi: 10.1016/j.bmcl.2005.10.054. Epub 2005 Nov 10.


The highly selective agonists of the A(3) adenosine receptor (AR), Cl-IB-MECA (2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine), and its 4'-thio analogue, were successfully converted into selective antagonists simply by appending a second N-methyl group on the 5'-uronamide position. The 2-chloro-5'-(N,N-dimethyl)uronamido analogues bound to, but did not activate, the human A(3)AR, with K(i) values of 29 nM (4'-O) and 15 nM (4'-S), showing >100-fold selectivity over A(1), A(2A), and A(2B)ARs. Competitive antagonism was demonstrated by Schild analysis. The 2-(dimethylamino)-5'-(N,N-dimethyl)uronamido substitution also retained A(3)AR selectivity but lowered affinity.

Publication types

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

MeSH terms

  • Adenosine / chemistry
  • Adenosine / pharmacology*
  • Adenosine A3 Receptor Agonists
  • Adenosine A3 Receptor Antagonists
  • Amides / chemistry*
  • Animals
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Furans / chemistry*
  • Humans
  • Receptor, Adenosine A3 / chemistry*
  • Ribose / chemistry*
  • Structure-Activity Relationship


  • Adenosine A3 Receptor Agonists
  • Adenosine A3 Receptor Antagonists
  • Amides
  • Furans
  • Receptor, Adenosine A3
  • Ribose
  • Adenosine
  • furan