Modulation of A_2B adenosine receptor by 1-Benzyl-3-ketoindole derivatives

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• 作者：Sabrina Taliani ; Maria Letizia Trincavelli ; Barbara Cosimelli ; Sonia Laneri ; Elda Severi ; Elisabetta Barresi ; Isabella Pugliesi ; Simona Daniele ; Chiara Giacomelli ; Giovanni Greco ; Ettore Novellino ; Claudia Martini ; Federico Da Settimo
• 关键词：1-Benzyl-3-ketoindole derivatives ; A2B adenosine receptor ; Positive modulators ; Negative modulators ; GPCR modulators ; Ligand&ndash ; receptor interaction
• 刊名：European Journal of Medicinal Chemistry
• 出版年：November, 2013
• 年：2013
• 卷：69
• 期：Complete
• 页码：331-337
• 全文大小：435 K

文摘

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.