Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A(3) adenosine receptor antagonists.
1H,3H-Pyrido[2,1-f]purine-2,4-diones, which can be described as fused xanthine structures, have been synthesized by a novel synthetic procedure, and their affinities for the human adenosine A(1), A(2A), and A(3) receptors have been evaluated in radioligand binding studies. The synthetic procedure employed was developed in our laboratory and involved a two-step one-pot reaction that consists of the treatment of 6-aminouracil derivatives with N-bromosuccinimide to generate a 5,5-dibromo-6-imino intermediate that reacts "in situ" with pyridine, 4-methoxypyridine, 4-tert-butylpyridine, or 4-phenylpyridine to afford the corresponding 1H,3H-pyrido[2,1-f]purine-2,4-diones (2-5). Functionalization at the N(3) position in compounds 2-5 was performed by reaction with DBU and different alkyl, alkenyl, alkynyl, or benzyl halides. Binding studies at human adenosine A(1), A(2A), and A(3) receptors revealed significant antagonist effects in the low nanomolar range, in particular against the A(3) receptor. Thus, the 1-benzyl-3-propyl-1H,3H-pyrido[2,1-f]purine-2,4-dione derivative 6, which can be considered a lead compound in this series, exhibited a K(i) value of 4.0 +/- 0.3 nM against the hA(3) receptor. Because xanthine derivatives have traditionally been considered poor A(3) antagonists, the described pyrido[2,1-f]purine-2,4-dione derivatives represent a new family of adenosine receptor antagonists which deserves further exploration.
Priego
Eva-María
EM
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
von Frijtag Drabbe Kuenzel
Jacobien
J
IJzerman
Ad P
AP
Camarasa
María-José
MJ
Pérez-Pérez
María-Jesús
MJ
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D058915:Purinergic P1 Receptor Antagonists; D011688:Purinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship
C463490:1-benzyl-3-propyl-1H,3H-pyrido(2,1-f)purine-2,4-dione; D058915:Purinergic P1 Receptor Antagonists; D011688:Purinones; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1