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.

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作   者：

Colotta V;  Catarzi D;  Varano F;  Filacchioni G;  Martini C;  Trincavelli L;  Lucacchini A; 

作者机构：

Universita di Firenze;  6;  Fiorentino;  Italy;  Via Ugo Schiff;  Polo Scientifico;  50019 Sesto (FJ);  Dipartimento di Scienze Farmaceutiche; 

关键词：

derivatives;  Synthesis;  binding; 

期刊名称：

Bioorganic and medicinal chemistry

i s s n：

0968-0896

年卷期：

2003 年 11 卷 24 期

页   码：

5509-5518

页   码：

摘   要：

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, thussuggesting 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.