Does the combination of optimal substitutions at the C²-, N⁵- and N⁸-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A₃ adenosine receptors?

In an attempt to study the optimal combination of a phenyl ring at the C²-position and different substituents at the N⁵- and N⁸-positions towards the selective modulation of human A₃ adenosine receptors (hA₃AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidin...

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Published in:Bioorganic & medicinal chemistry 2011-10, Vol.19 (20), p.6120-6134
Main Authors: Cheong, Siew Lee, Dolzhenko, Anton V, Paoletta, Silvia, Lee, Evelyn Pei Rong, Kachler, Sonja, Federico, Stephanie, Klotz, Karl-Norbert, Dolzhenko, Anna V, Spalluto, Giampiero, Moro, Stefano, Pastorin, Giorgia
Format: Article
Language:English
Subjects:
adenosine
Animals
Biological and medical sciences
chemistry
CHO Cells
Cricetinae
Humans
Medical sciences
Models, Molecular
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Pyrazoles - chemistry
Pyridines - chemistry
Receptor, Adenosine A3 - chemistry
receptors
Structure-Activity Relationship
Triazoles - chemistry
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Summary:In an attempt to study the optimal combination of a phenyl ring at the C²-position and different substituents at the N⁵- and N⁸-positions towards the selective modulation of human A₃ adenosine receptors (hA₃AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N⁸ and chains of variable length at N⁵. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA₃AR in the low nanomolar range. Compound 16 possessed the best hA₃AR affinity and selectivity profile (KᵢhA₃=1.33nM; hA₁/hA₃=4880; hA₂A/hA₃=1100) in the present series of 2-(substituted)phenyl-pyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA₃AR.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.08.026