Synthesis of 4-amino-6-(hetero)arylalkylamino-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as potent A(2A) adenosine receptor antagonists.
In previous papers (Colotta, V. et al. Arch. Pharm. Pharm. Med. Chem. 1999, 332, 39. Colotta, V. et al. J. Med. Chem. 2000, 43, 1158) we reported the synthesis and binding affinity at bovine (b) A(1) and A(2A) and human (h) A(3) adenosine receptors (ARs) of the 4-amino-6-benzylamino-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (compound A) which resulted in a potent and selective A(2A) AR antagonist. Compound A provided the lead compound of a series of 6- or 8-(hetero)arylalkylamino-4-amino-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives (compounds 1-20) which are the object of this paper. Most of the newly synthesized compounds are inactive at hA(3) ARs while they possess both nanomolar bA(2A) affinities and different degrees of bA(2A) versus bA(1) selectivity. The binding data show that hydrophilic substituents on the benzyl moiety are the most profitable for bA(2A) receptor affinity. Furthermore, their steric hindrance seems to play an important role for the bA(2A) AR interaction, thus suggesting that the 6-aralkylamino moiety of these ligands interacts with a size-limited binding pocket of this AR subtype. Thus, the SAR studies provided us some new insights about the structural requirements of the bA(2A) AR recognition site.
Colotta
Vittoria
V
Dipartimento di Scienze Farmaceutiche, Polo Scientifico, Universitá di Firenze, Via Ugo Schiff, 6, 50019 Sesto (FJ), Fiorentino, Italy. vittoria.colotta@unifi.it
Catarzi
Daniela
D
Varano
Flavia
F
Filacchioni
Guido
G
Martini
Claudia
C
Trincavelli
Letizia
L
Lucacchini
Antonio
A
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D006801:Humans; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D011799:Quinazolines; D014230:Triazoles