title: 3-aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A₂B adenosine receptor antagonists.
abstract: In an effort to identify novel ligands possessing high affinity and selectivity for the A(2B) AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A(1) AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A(2B) AR, no affinity at A(3) AR, and various degrees of selectivity toward A(1) and A(2A) ARs. Investigation of a new series featuring modified substituents at the 10-position (4'-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A(2B) AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A(2A) AR, conferring high A(2B)/A(2A) AR selectivity. Derivative 13 (X = Cl, R = C(6)H(5)) is the most potent and selective compound, with an IC(50) of 3.10 nM at A(2B) AR and no affinity at A(1), A(2A), and A(3) ARs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. taliani@farm.unipi.it
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Isabella
authors.initials: I
authors.lastname: Pugliesi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Silvia
authors.initials: S
authors.lastname: Salerno
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011869:Radioligand Assay; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C572347:7-chloro-3,10-diphenyl(1,2,4)triazino(4,3-a)benzimidazol-4(10H)-one; D058917:Adenosine A2 Receptor Antagonists; D001562:Benzimidazoles; D043704:Receptor, Adenosine A2B; D014227:Triazines; D000242:Cyclic AMP