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

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 A3AR selectivity but lowered affinity. (c) 2005 Elsevier Ltd. All rights reserved.