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
journal contributionposted on 09.07.2009, 00:00 by Thomas Borrmann, Sonja Hinz, Daniela C. G. Bertarelli, Wenjin Li, Nicole C. Florin, Anja B. Scheiff, Christa E. Müller
A new series of 1-alkyl-8-(piperazine-1-sulfonyl)phenylxanthines was designed, synthesized, and characterized in radioligand binding and functional assays at A2B adenosine receptors. A2B 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)xanthine (24, PSB-09120, Ki (human A2B) = 0.157 nM) and 8-(4-(4-(4-chlorobenzyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (17, PSB-0788, Ki (human A2B) = 0.393 nM). Moreover, 8-(4-(4-(4-chlorophenyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (35, PSB-603) was developed as an A2B-specific antagonist exhibiting a Ki value of 0.553 nM at the human A2B receptor and virtually no affinity for the human and rat A1 and A2A and the human A3 receptors up to a concentration of 10 μM. 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 A2B receptors (KD human A2B 0.403 nM, mouse A2B 0.351 nM).
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2B adenosine receptorsradioligand bindingsubnanomolar affinity2B Receptor Antagonists2B receptor2AKD0.157 nM2B 0.403 nM3 receptors2B receptors0.553 nM2B 0.351 nMcompetition studies10 μ MNew RadioligandKi value2B antagonistPSB2B antagonists0.393 nMSubtype SpecificityAtritiated formSubnanomolar Affinity