title: 5,7-Disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as pharmacological tools to explore the antagonist selectivity profiles toward adenosine receptors.
abstract: The structure-activity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes (10: KihA1 = 94.6 nM; KihA2A = 1.11 nM; IC50hA2B = 2214 nM; KihA3 = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki = 1.44 nM; hA1/hA2A = 216.0; hA3/hA2A = 20.6). This trend diverges from the analysis on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA2A AR.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federico
authors.affiliation: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.affiliation: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Porta
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Redenti
authors.affiliation: Department of Pharmacy, National University of Singapore, 3 Science Drive 2, 117543 Singapore.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pastorin
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.affiliation: Institut für Pharmakologie und Toxicologie, Universität of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
authors.forename: Karl Norbert
authors.initials: KN
authors.lastname: Klotz
authors.affiliation: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy. Electronic address: stefano.moro@unipd.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Piazzale Europa 1, 34127 Trieste, Italy. Electronic address: spalluto@units.it.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058915:Purinergic P1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000611515:(1,2,4)triazolo(1,5-a)(1,3,5)triazine; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles
keywords: Adenosine receptors; Antagonists; G protein-coupled receptor; Molecular modeling; Structure activity relationship; Triazolo-triazine