Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bmc.2010.02.039
Title: Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives as adenosine receptor antagonists: A preliminary inspection of ligand-receptor recognition process
Authors: Pastorin, G. 
Federico, S.
Paoletta, S.
Corradino, M.
Cateni, F.
Cacciari, B.
Klotz, K.-N.
Gao, Z.-G.
Jacobson, K.A.
Spalluto, G.
Moro, S.
Keywords: Adenosine receptor antagonists
G Protein-coupled receptors
Ligand-receptor modeling studies
Triazolo-triazine
Issue Date: 1-Apr-2010
Citation: Pastorin, G., Federico, S., Paoletta, S., Corradino, M., Cateni, F., Cacciari, B., Klotz, K.-N., Gao, Z.-G., Jacobson, K.A., Spalluto, G., Moro, S. (2010-04-01). Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives as adenosine receptor antagonists: A preliminary inspection of ligand-receptor recognition process. Bioorganic and Medicinal Chemistry 18 (7) : 2524-2536. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bmc.2010.02.039
Abstract: A new series of triazolotriazines variously substituted at the C5 and N7 (5-25) positions was synthesized and fully characterized at the four adenosine receptor (AR) subtypes. In particular, arylacetyl or arylcarbamoyl moieties were introduced at the N7 position, which enhanced affinity at the hA2B and hA3 ARs, respectively, when utilized on the pyrazolo-triazolopyrimidine nucleus as we reported in the past. In general, compounds with a free amino group at the 7 position (5, 6), showed good affinity at the rat (r) A2A AR (range 18.3-96.5 nM), while the introduction of a phenylcarbamoyl moiety at the N7 position (12, 19, 24) slightly increased the affinity at the hA3 AR (range 311-633 nM) with respect to the unsubstituted derivatives. The binding profiles of the synthesized analogues seemed to correlate with the substitutions at the C5 and N7 positions. At the hA2B AR, derivative 5, which contained a free amino group at the 7 position, was the most potent (EC50 3.42 μM) and could represent a starting point for searching new non-xanthine hA2B AR antagonists. Molecular models of the rA2A and hA3 ARs were constructed by homology to the recently reported crystallographic structure of the hA2A AR. A preliminary receptor-driven structure-activity relationship (SAR) based on the analysis of antagonist docking has been provided. © 2010 Elsevier Ltd. All rights reserved.
Source Title: Bioorganic and Medicinal Chemistry
URI: http://scholarbank.nus.edu.sg/handle/10635/106395
ISSN: 09680896
DOI: 10.1016/j.bmc.2010.02.039
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