| 19569717 |
Borrmann T, Hinz S, Bertarelli DC, Li W, Florin NC, Scheiff AB, Muller CE: 1-alkyl-8-(piperazine-1-sulfonyl) phenylxanthines: development and characterization of adenosine A2B receptor antagonists and a new radioligand with subnanomolar affinity and subtype specificity. J Med Chem. 2009 Jul 9;52(13):3994-4006.
A new series of 1-alkyl-8-(piperazine-1-sulfonyl) phenylxanthines was designed, synthesized, and characterized in radioligand binding and functional assays at A (2B) adenosine receptors. A (2B) antagonists with subnanomolar affinity and high selectivity were discovered. The most potent compounds were 1-ethyl-8-(4-(4-(4-trifluoromethylbenzyl) piperazine-1-sulfonyl) phenyl) xant hine (24, PSB-09120, K (i) (human A (2B)) = 0.157 nM) and 8-(4-(4-(4-chlorobenzyl) piperazine-1-sulfonyl) phenyl)-1-propylxanthine (17, PSB-0788, K (i) (human A (2B)) = 0.393 nM). Moreover, 8-(4-(4-(4-chlorophenyl) piperazine-1-sulfonyl) phenyl)-1-propylxanthine (35, PSB-603) was developed as an A (2B)-specific antagonist exhibiting a K (i) value of 0.553 nM at the human A (2B) receptor and virtually no affinity for the human and rat A (1) and A (2A) and the human A (3) receptors up to a concentration of 10 microM. A tritiated form of the compound was prepared as a new radioligand and characterized in kinetic, saturation, and competition studies. It was shown to be a useful pharmacological tool for the selective labeling of human as well as rodent A (2B) receptors (K (D) human A (2B) 0.403 nM, mouse A (2B) 0.351 nM). |
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