Modulation of A2B adenosine receptor by 1-Benzyl-3-ketoindole derivatives.
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.
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Sabrina
S
Taliani
Maria Letizia
ML
Trincavelli
Barbara
B
Cosimelli
Sonia
S
Laneri
Elda
E
Severi
Elisabetta
E
Barresi
Isabella
I
Pugliesi
Simona
S
Daniele
Chiara
C
Giacomelli
Giovanni
G
Greco
Ettore
E
Novellino
Claudia
C
Martini
Federico
F
Da Settimo
D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007211:Indoles; D043704:Receptor, Adenosine A2B
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