Substituted pyrazolo[3,4-b]pyridines as potent A1 adenosine antagonists: synthesis, biological evaluation, and development of an A1 bovine receptor model.
Sixty-eight new substituted pyrazolo[3,4-b]pyridine derivatives were synthesized and tested for enriching a library of active A(1) adenosine receptor (AR) antagonists belonging to the same class. These compounds were also used as an external test set to check the reliability of a 3D QSAR model recently reported by us. To investigate the binding mode of pyrazolopyridine derivatives, a model of the bovine A(1)AR (bA(1)AR) was developed by a novel homology modeling approach and used to evaluate the main interactions of the ligands with the receptor through docking studies. Results suggest important interactions of the ligands mainly with L3.33(88), T3.36(91), Q3.37(92) and H6.52(251), in agreement with mutagenesis data. The racemic mixture of the most active compound was separated into the corresponding enantiomers which showed a bA(1)AR affinity in the nanomolar range, with the R enantiomer sevenfold more active than the S enantiomer, according to results derived from calculations on the receptor model. Analysis of the bovine/human A(1)AR affinity profile of ligands supported the hypothesis that such receptors should be characterized by a different size of their binding site, responsible for the different affinity of the antagonists.
Tuccinardi
Tiziano
T
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy. schensil@unige.it
Schenone
Silvia
S
Bondavalli
Francesco
F
Brullo
Chiara
C
Bruno
Olga
O
Mosti
Luisa
L
Zizzari
Alessandra Tania
AT
Tintori
Cristina
C
Manetti
Fabrizio
F
Ciampi
Osele
O
Trincavelli
Maria Letizia
ML
Martini
Claudia
C
Martinelli
Adriano
A
Botta
Maurizio
M
D058916:Adenosine A1 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D043682:Receptor, Adenosine A1 / Q000737:chemistry*; D043684:Receptor, Adenosine A3 / Q000737:chemistry; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013997:Time Factors
D058916:Adenosine A1 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011720:Pyrazoles; D011725:Pyridines; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; C447480:pyrazolo(3,4-b)pyridine