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PLoS One. 2015 Dec 1;10(12):e0143504. doi: 10.1371/journal.pone.0143504. eCollection 2015.

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.

Author information

  • 1Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy.
  • 2Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy.
  • 3Institut für Pharmakologie und Toxicologie, Universität Würzburg, Würzburg, Germany.
  • 4Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Ferrara, Italy.

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.

PMID:
26625265
PMCID:
PMC4666649
DOI:
10.1371/journal.pone.0143504
[PubMed - indexed for MEDLINE]
Free PMC Article
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