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?
2011
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
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.
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