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