title: 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?
abstract: In an attempt to study the optimal combination of a phenyl ring at the C(2)-position and different substituents at the N(5)- and N(8)-positions towards the selective modulation of human A(3) adenosine receptors (hA(3)AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N(8) and chains of variable length at N(5). Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA(3)AR in the low nanomolar range. Compound 16 possessed the best hA(3)AR affinity and selectivity profile (K(i)hA(3)=1.33 nM; hA(1)/hA(3)=4880; hA(2A)/hA(3)=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 hA(3)AR.
authors: Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Block S15, #05-PI-03, 117543 Singapore, Singapore.
authors: Siew Lee
authors: SL
authors: Cheong
authors: Anton V
authors: AV
authors: Dolzhenko
authors: Silvia
authors: S
authors: Paoletta
authors: Evelyn Pei Rong
authors: EP
authors: Lee
authors: Sonja
authors: S
authors: Kachler
authors: Stephanie
authors: S
authors: Federico
authors: Karl-Norbert
authors: KN
authors: Klotz
authors: Anna V
authors: AV
authors: Dolzhenko
authors: Giampiero
authors: G
authors: Spalluto
authors: Stefano
authors: S
authors: Moro
authors: Giorgia
authors: G
authors: Pastorin
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D011720:Pyrazoles; D011725:Pyridines; D043684:Receptor, Adenosine A3; D014230:Triazoles