Borrmann Thomas, Hinz Sonja, Bertarelli Daniela C G, Li Wenjin, Florin Nicole C, Scheiff Anja B, Müller Christa E
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, D-53121 Bonn, Germany.
J Med Chem. 2009 Jul 9;52(13):3994-4006. doi: 10.1021/jm900413e.
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)xanthine (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).
设计、合成了一系列新的1-烷基-8-(哌嗪-1-磺酰基)苯基黄嘌呤，并通过A(2B)腺苷受体的放射性配体结合和功能测定对其进行了表征。发现了具有亚纳摩尔亲和力和高选择性的A(2B)拮抗剂。最有效的化合物是1-乙基-8-(4-(4-(4-三氟甲基苄基)哌嗪-1-磺酰基)苯基)黄嘌呤(24，PSB-09120，K(i)(人A(2B)) = 0.157 nM)和8-(4-(4-(4-氯苄基)哌嗪-1-磺酰基)苯基)-1-丙基黄嘌呤(17，PSB-0788，K(i)(人A(2B)) = 0.393 nM)。此外，8-(4-(4-(4-氯苯基)哌嗪-1-磺酰基)苯基)-1-丙基黄嘌呤(35，PSB-603)被开发为一种A(2B)特异性拮抗剂，在人A(2B)受体上的K(i)值为0.553 nM，在浓度高达10 microM时对人和大鼠的A(1)、A(2A)以及人A(3)受体几乎没有亲和力。制备了该化合物的氚标记形式作为一种新的放射性配体，并在动力学、饱和和竞争研究中对其进行了表征。结果表明，它是一种用于选择性标记人和啮齿动物A(2B)受体的有用药理学工具(K(D)人A(2B) 0.403 nM，小鼠A(2B) 0.351 nM)。
