N6-cycloalkyl-2-phenyl-3-deaza-8-azaadenines: a new class of A1 adenosine receptor ligands. A comparison with the corresponding adenines and 8-azaadenines.
Several 9-benzyl-N6-cycloalkyl-2-phenyladenines, 9-benzyl-N6-cycloalkyl-2-phenyl-8-azaadenines and 4-cycloalkylamino-1-benzyl-6-phenyl-1H-1,2,3-triazolo[4,5-c]pyridines were prepared and assayed as A1 adenosine receptor ligands. The 1H-1,2,3-triazolo[4,5-c]pyridines were obtained starting from N,N-diethyl-1-benzyl-4-carboxyamido-5-methyl-1H-1,2,3-triazole by lithiation in anhydrous tetrahydrofurane in the presence of benzonitrile. The usual work up afforded the isolation of 1-benzyl-6-phenyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-one which was treated with phosphorous oxychloride and cycloalkylamines. Some compounds showed high affinity and selectivity and the trend of Ki values corresponds to the series of 9-benzyl-N6-cycloalkyl-2-phenyladenines and 9-benzyl-N6-cycloalkyl-2-phenyl-8-azaadenines, therefore they can be considered bioisosteres. The affinity data permitted us to ascertain the role and the importance of the N3 in the adenine or 8-azaadenine moiety in the receptor binding and to study the dimension of the receptor lipophilic pocket which is filled by the N6 substituent of adenosine derivatives.
Biagi
Giuliana
G
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno, 6-56126 Pisa, Italy.
Giorgi
Irene
I
Livi
Oreste
O
Nardi
Antonio
A
Pacchini
Federica
F
Scartoni
Valerio
V
Lucacchini
Antonio
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002417:Cattle; D008024:Ligands; D011485:Protein Binding / Q000502:physiology; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D043682:Receptor, Adenosine A1; D000225:Adenine; C006654:8-azaadenine