SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF DEAZAXANTHINES - ANALOGS OF POTENT A(1-)-ADENOSINE AND A(2)-ADENOSINE RECEPTOR ANTAGONISTS

A set of 22 9-deazaxanthines (pyrrolo[3,2-d]pyrimidine-2,4-diones) and three 7-deazaxanthines (pyrrolo[2,3-d] pyrimidine-2,4-diones) with va rious substituents in the 1-, 3-, 7- or 9-, and 8-positions was synthe sized and investigated in A1 and A2a adenosine receptor binding assays at rat brain cortical membranes and rat brain striatal membranes, res pectively. 9-Deazaxanthines showed structure-activity relationships th at were similar to those of xanthines. They were about equipotent to t he corresponding xanthines at A2a adenosine receptors. 9-Deazaxanthine s were generally at least 2-3-fold more potent than xanthines at A1 re ceptors and therefore exhibited higher A1 selectivities compared to th e xanthines. 1,3-Dimethyl-8-(2-naphthyl)-9-deazaxanthine (19e) showed high affinty (K-i = 26 nM) and selectivity for A1 adenosine receptors. A hydroxyl function at N7 of 9-deazaxanthines was unfavorable for A1 and A2a receptor binding. 7-Deazaxanthines were considerably less pote nt compared to xanthines and to 9-deazaxanthines at both receptor subt ypes.