The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1<i>H</i>-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-<i>e</i>][1,2,4]Triazolo[1,5-<i>c</i>]Pyrimidine Derivatives Stephanie Federico Sara Redenti Mattia Sturlese Antonella Ciancetta Sonja Kachler Karl-Norbert Klotz Barbara Cacciari Stefano Moro Giampiero Spalluto 10.1371/journal.pone.0143504 https://plos.figshare.com/articles/dataset/The_Influence_of_the_1_3_Trifluoromethyl_Benzyl_1_H_Pyrazole_4_yl_Moiety_on_the_Adenosine_Receptors_Affinity_Profile_of_Pyrazolo_4_3_e_1_2_4_Triazolo_1_5_c_Pyrimidine_Derivatives/1615842 <div><p>A new series of pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]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)-1<i>H</i>-pyrazole, a group believed to confer potency and selectivity toward the human (h) A<sub>2B</sub> adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl)benzyl)-1<i>H</i>-pyrazol-4-yl)-1,3-dimethyl-1<i>H</i>-purine-2,6(3<i>H</i>,7<i>H</i>)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA<sub>2B</sub> AR but they displayed affinity at the hA<sub>3</sub> AR in the nanomolar range. The best compound of the series (<b>6</b>) shows both high affinity (hA<sub>3</sub> AR K<sub>i</sub> = 11 nM) and selectivity (A<sub>1</sub>/A<sub>3</sub> and A<sub>2A</sub>/A<sub>3</sub> > 9090; A<sub>2B</sub>/A<sub>3</sub> > 909) at the hA<sub>3</sub> 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)-1<i>H</i>-pyrazole on the binding at the four ARs.</p></div> 2015-12-01 16:00:15 adenosine receptor subtypes affinity 2a compound hA 3 AR 2B adenosine receptor PTP scaffold C 2 position AR subtypes nanomolar range Adenosine Receptors Affinity Profile CTV 6975 docking study 11 nM hA 3 AR Ki docking protocol cvt selectivity profile hA 2B AR