Allosteric modulators of human A2B adenosine receptor

• Published in: Biochimica et biophysica acta Vol. 1840; no. 3; pp. 1194 - 1203
• Main Authors: Trincavelli, Maria Letizia, Giacomelli, Chiara, Daniele, Simona, Taliani, Sabrina, Cosimelli, Barbara, Laneri, Sonia, Severi, Elda, Barresi, Elisabetta, Pugliesi, Isabella, Greco, Giovanni, Novellino, Ettore, Da Settimo, Federico, Martini, Claudia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2014
• Subjects: 1-Benzyl-3-ketoindole derivatives; A2B adenosine receptor; adenosine; Adenosine-5'-(N-ethylcarboxamide) - pharmacology; agonists; Allosteric Regulation; Cyclic AMP - physiology; GPCR allosteric modulators; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; inflammation; ischemia; Ligand–receptor interaction; Negative allosteric modulators; Positive allosteric modulators; purinergic receptors; Receptor, Adenosine A2B - drug effects; Receptor, Adenosine A2B - metabolism; Positive allosteric modulators; [3H]NECA; 1-Benzyl-3-ketoindole derivatives; CHO; [3H]MRS 1754; cAMP; AR; DMEM; A2B adenosine receptor; Negative allosteric modulators; DMAP; GPCR; GPCR allosteric modulators; Ro 20-1724; ADA; Ligand–receptor interaction; BAY 60-6583; [35S]GTPγS; [H]MRS 1754; A(2B) adenosine receptor; 4-dimethylaminopyridine; [H]5′-N-ethylcarboxamideadenosine; adenosine receptor; G protein-coupled receptor; [S]guanosine 5′-O-[gamma-thio]triphosphate; [H]N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide; 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide; [S]GTPγS; 3′,5′-cyclic adenosine monophosphate; Dulbecco's Modified Eagle Medium; [H]NECA; 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone; Chinese hamster ovary; adenosine deaminase
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.12.021

Among adenosine receptors (ARs) the A2B subtype exhibits low affinity for the endogenous agonist compared with the A1, A2A, and A3 subtypes and is therefore activated when concentrations of adenosine increase to a large extent following tissue damages (e.g. ischemia, inflammation). For this reason, A2B AR represents an important pharmacological target. We evaluated seven 1-benzyl-3-ketoindole derivatives (7–9) for their ability to act as positive or negative allosteric modulators of human A2B AR through binding and functional assays using CHO cells expressing human A1, A2A, A2B, and A3 ARs. The investigated compounds behaved as specific positive or negative allosteric modulators of human A2B AR depending on small differences in their structures. The positive allosteric modulators 7a,b and 8a increased agonist efficacy without any effect on agonist potency. The negative allosteric modulators 8b,c and 9a,b reduced agonist potency and efficacy. A number of 1-benzyl-3-ketoindole derivatives were pharmacologically characterized as selective positive (7a,b) or negative (8c, 9a,b) allosteric modulators of human A2B AR. The 1-benzyl-3-ketoindole derivatives 7–9 acting as positive or negative allosteric modulators of human A2B AR represent new pharmacological tools useful for the development of therapeutic agents to treat pathological conditions related to an altered functionality of A2B AR. •We identified allosteric modulators of the human A2B adenosine receptor (A2B AR).•All are unable to bind A2A and A3 ARs and show low or no affinity towards A1 AR.•The new compounds are 1-benzyl-3-ketoindole derivatives.•Small structural differences lead to positive or negative allosteric modulation.•They may help to explore the therapeutic potential of A2B AR allosteric modulators.