title: Exploring the directionality of 5-substitutions in a new series of 5-alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine as a strategy to design novel human a(3) adenosine receptor antagonists.
abstract: The structure-activity relationship (SAR) of new 5-alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as antagonists of the A(3) adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A(3) AR. All the synthesized compounds showed affinity for the hA(3) AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (S) α-phenylethylamino moiety at the 5 position (26, K(i) hA(3) = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N(5) position toward the extracellular environment.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Piazzale Europa 1, I-34127 Trieste, Italy.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federico
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.forename: Davide
authors.initials: D
authors.lastname: Sabbadin
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pastorin
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Karl Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
mesh_terms: D000262:Adenylyl Cyclases; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058915:Purinergic P1 Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry*; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D000262:Adenylyl Cyclases