Structure‐affinity relationships of adenosine A 2B receptor ligands

Many selective and high affinity agonists and antagonists have been developed for the adenosine A 1 , A 2A , and A 3 receptors. Very recently such compounds have been identified for the adenosine A 2B receptors. This review presents an overview of the structure‐affinity relationships of antagonists and agonists for this receptor subtype as published in the scientific and patent literature. To date the most selective >370‐fold, high affinity adenosine A 2B receptor antagonist is the xanthine analog, compound 16 (8‐(1‐(3‐phenyl‐1,2,4‐oxadiazol‐5‐yl)methyl)‐1 H ‐pyrazol‐4‐yl)‐1,3‐dipropyl‐1 H ‐purine‐2,6(3 H ,7 H )‐dione). The pyrrolopyrimidine analog OSIP339391 ( 73 ) is slightly less selective, 70‐fold, but has a higher affinity 0.41 nM compared to 1 nM for compound 16 . Other promising classes of compounds with selectivities ranging from 10‐ to 160‐fold and affinities ranging from 3 to 112 nM include triazolo, aminothiazole, quinazoline, and pyrimidin‐2‐amine analogs. Progress has also been achieved concerning the development of selective high affinity agonists for the adenosine A 2B receptor. For years the most potent, albeit non‐selective adenosine A 2B receptor agonist was ( S )PHPNECA ( 88 ). Last year, a new class of non‐ribose ligands was reported. Several compounds displayed selectivity with respect to adenosine A 2A and A 3 receptors. In addition, full and partial agonists for the adenosine A 2B receptor were identified with EC 50 values of 10 nM (LUF5835, 103 ) and 9 nM (LUF5845, 105 ), respectively. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 667–698, 2006