Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Eur J Med Chem. 2013 Nov;69:331-7. doi: 10.1016/j.ejmech.2013.09.001. Epub 2013 Sep 8.
We have disclosed a series of 1-benzyl-3-ketoindole derivatives acting as either positive or negative modulators of the human A(2B) adenosine receptor (A(2B) AR) depending on small differences in their side chain. The new compounds were designed taking into account structural similarities between AR antagonists and ligands of the GABA(A)/benzodiazepine receptor. All compounds resulted totally inactive at A(2A) and A₃ ARs and showed small (8a,b) or none (7a,b, 8c and 9a,b) affinity for A₁ AR. When tested on A(2B) AR-transfected CHO cells, 7a,b and 8a acted as positive modulators, whereas 8b,c and 9a,b acted as negative modulators, enhancing or weakening the NECA-induced increase of cAMP levels, respectively. Compounds 7-9 might be regarded as useful biological and pharmacological tools to explore the therapeutic potential of A(2B) AR modulators, while their 3-ketoindole scaffold might be taken as a reference to design new analogs.
我们已经披露了一系列 1-苄基-3-酮吲哚衍生物，它们可以作为人 A(2B)腺苷受体 (A(2B)AR) 的正调节剂或负调节剂，具体取决于其侧链的微小差异。新化合物的设计考虑了 AR 拮抗剂和 GABA(A)/苯二氮䓬受体配体之间的结构相似性。所有化合物在 A(2A)和 A₃AR 上完全没有活性，并且对 A₁AR 的亲和力很小（8a,b）或没有（7a,b, 8c 和 9a,b）。当在转染 A(2B)AR 的 CHO 细胞上进行测试时，7a,b 和 8a 表现为正调节剂，而 8b,c 和 9a,b 表现为负调节剂，分别增强或减弱 NECA 诱导的 cAMP 水平增加。化合物 7-9 可能被视为探索 A(2B)AR 调节剂治疗潜力的有用的生物学和药理学工具，而它们的 3-酮吲哚骨架可能被用作设计新类似物的参考。
