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Eur J Med Chem. 2016 Jan 27;108:529-41. doi: 10.1016/j.ejmech.2015.12.019. Epub 2015 Dec 15.

5,7-Disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as pharmacological tools to explore the antagonist selectivity profiles toward adenosine receptors.

Author information

  • 1Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
  • 2Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.
  • 3Department of Pharmacy, National University of Singapore, 3 Science Drive 2, 117543 Singapore.
  • 4Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
  • 5Institut für Pharmakologie und Toxicologie, Universität of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
  • 6Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy. Electronic address: stefano.moro@unipd.it.
  • 7Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Piazzale Europa 1, 34127 Trieste, Italy. Electronic address: spalluto@units.it.

Abstract

The structure-activity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes (10: KihA1 = 94.6 nM; KihA2A = 1.11 nM; IC50hA2B = 2214 nM; KihA3 = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki = 1.44 nM; hA1/hA2A = 216.0; hA3/hA2A = 20.6). This trend diverges from the analysis on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA2A AR.

KEYWORDS:

Adenosine receptors; Antagonists; G protein-coupled receptor; Molecular modeling; Structure activity relationship; Triazolo-triazine

PMID:
26717203
DOI:
10.1016/j.ejmech.2015.12.019
[PubMed - indexed for MEDLINE]
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