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Eur J Med Chem. 2013 Nov;69:331-7. doi: 10.1016/j.ejmech.2013.09.001. Epub 2013 Sep 8.

Modulation of A2B adenosine receptor by 1-Benzyl-3-ketoindole derivatives.

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Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.


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.


1-Benzyl-3-ketoindole derivatives; 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5′-N-methyluronamide; 3′,5′-cyclic adenosine monophosphate; 4-dimethylaminopyridine; A(2B) adenosine receptor; ADA; AR; CHO; Chinese hamster ovary; Cl-IBMECA; DMAP; DMEM; Dulbecco's Modified Eagle Medium; G-protein coupled receptors; GPCR modulators; GPCRs; Ligand–receptor interaction; Negative modulators; Positive modulators; SEM; [(125)I]4-aminobenzyl-5′-N-methylcarboxamidoadenosine; [(125)I]AB-MECA; [(3)H]5′-N-ethylcarboxamideadenosine; [(3)H]8-cyclopentyl-1,3-dipropylxanthine; [(3)H]DPCPX; [(3)H]NECA; adenosine deaminase; adenosine receptor; cAMP; standard error of mean

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