title: The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1H-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine Derivatives.
abstract: A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A2B adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA2B AR but they displayed affinity at the hA3 AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA3 AR Ki = 11 nM) and selectivity (A1/A3 and A2A/A3 > 9090; A2B/A3 > 909) at the hA3 AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federico
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Redenti
authors.affiliation: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Sturlese
authors.affiliation: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.affiliation: Institut für Pharmakologie und Toxicologie, Universität Würzburg, Würzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.affiliation: Institut für Pharmakologie und Toxicologie, Universität Würzburg, Würzburg, Germany.
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Ferrara, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.affiliation: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D018047:Receptors, Purinergic P1; C031280:pyrazole; C030986:pyrimidine