title: Allosteric modulators of human A2B adenosine receptor.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: barbara.cosimelli@unina.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Laneri
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Severi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Pugliesi
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: giovanni.greco@unina.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000494:Allosteric Regulation; D000242:Cyclic AMP / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D043704:Receptor, Adenosine A2B / Q000187:drug effects* / Q000378:metabolism
chemical_list: D043704:Receptor, Adenosine A2B; D019830:Adenosine-5'-(N-ethylcarboxamide); D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP
keywords: 1-Benzyl-3-ketoindole derivatives; 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide; 3′,5′-cyclic adenosine monophosphate; 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone; 4-dimethylaminopyridine; A(2B) adenosine receptor; ADA; AR; BAY 60-6583; CHO; Chinese hamster ovary; DMAP; DMEM; Dulbecco's Modified Eagle Medium; G protein-coupled receptor; GPCR; GPCR allosteric modulators; Ligand–receptor interaction; Negative allosteric modulators; Positive allosteric modulators; Ro 20-1724; [(3)H]5′-N-ethylcarboxamideadenosine; [(3)H]MRS 1754; [(3)H]N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide; [(3)H]NECA; [(35)S]GTPγS; [(35)S]guanosine 5′-O-[gamma-thio]triphosphate; adenosine deaminase; adenosine receptor; cAMP