Novel potent and highly selective human A(3) adenosine receptor antagonists belonging to the 4-amido-2-arylpyrazolo[3,4-c]quinoline series: molecular docking analysis and pharmacological studies.
The study of novel 2-arylpyrazolo[3,4-c]quinolin-4-(hetero)arylamides, designed as human (h) A(3) adenosine receptor antagonists, is reported. The new derivatives are endowed with nanomolar hA(3) receptor affinity and high selectivity versus hA(1), hA(2A) and hA(2B) receptors. Among the (hetero)aroyl residues introduced on the 4-amino group, the 2-furyl and 4-pyridyl rings turned out to be the most beneficial for hA(3) affinity (K(i)=3.4 and 5.0nM, respectively). An intensive molecular docking study to a rhodopsin-based homology model of the hA(3) receptor was carried out to obtain a 'structure-based pharmacophore model' that proved to be helpful for the interpretation of the observed affinities of the new hA(3) pyrazoloquinoline antagonists.
Colotta
Vittoria
V
Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Università di Firenze, Polo Scientifico, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy. vittoria.colotta@unifi.it
Capelli
Francesca
F
Lenzi
Ombretta
O
Catarzi
Daniela
D
Varano
Flavia
F
Poli
Daniela
D
Vincenzi
Fabrizio
F
Varani
Katia
K
Borea
Pier Andrea
PA
Dal Ben
Diego
D
Volpini
Rosaria
R
Cristalli
Gloria
G
Filacchioni
Guido
G
D058918:Adenosine A3 Receptor Antagonists; D000577:Amides; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012243:Rhodopsin; D013329:Structure-Activity Relationship
D058918:Adenosine A3 Receptor Antagonists; D000577:Amides; D011804:Quinolines; D012243:Rhodopsin