title: Synthesis and biological studies of a new series of 5-heteroarylcarbamoylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as human A3 adenosine receptor antagonists. Influence of the heteroaryl substituent on binding affinity and molecular modeling investigations.
abstract: Some pyrazolotriazolopyrimidines bearing different heteroarylcarbamoylamino moieties at the N5-position are described. We previously reported the synthesis of a water soluble compound with high potency and selectivity versus the human A3 adenosine receptor as antagonist, and herein we present an enlarged series of compounds related to the previously mentioned one. These compounds showed A3 adenosine receptor affinity in the nanomolar range and different levels of selectivity evaluated in radioligand binding assays at human A1, A2A, A2B, and A3 adenosine receptors. In particular, the effect of the heteroaryl substituents at the N5 position has been analyzed. This study allows us to recognize that the presence of a pyridinium moiety in this position not only increases water solubility but also improves or retains potency and selectivity at the human A3 adenosine receptors. In contrast, replacement of pyridine with different heterocycles produces loss of affinity and selectivity at the human A3 adenosine receptors. A molecular modeling study has been carried out with the aim to explain these various binding profiles.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Trieste, Piazzale Europa 1, I-34127 Trieste, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pastorin
authors.forename: Tatiana
authors.initials: T
authors.lastname: Da Ros
authors.forename: Chiara
authors.initials: C
authors.lastname: Bolcato
authors.forename: Christian
authors.initials: C
authors.lastname: Montopoli
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
mesh_terms: D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D014230:Triazoles