2,9-disubstituted-N6-(arylcarbamoyl)-8-azaadenines as new selective A3 adenosine receptor antagonists: synthesis, biochemical and molecular modelling studies.
A number of N6-(N-arylcarbamoyl)-2-substituted-9-benzyl-8-azaadenines, obtained by a modification of the synthetic scheme used to prepare selective A1 ligands, by only three or two steps, are described. At first we prepared a series of 2-phenyl-9-benzyl-8-azaadenines having as N6 substituent a variously substituted N-phenylcarbamoyl group. Some of these derivatives demonstrated good affinity towards the A3 subtype but low selectivity. Compounds having p-CF3, p-F and p-OCH3, as substituents on the phenylcarbamoyl group were selected as lead compounds for the second part of this study. Without modifying the N6 substituent, which would assure A3 affinity, we varied the 9 and 2 positions on these molecules to enhance selectivity. Some compounds having a p-methyl group on the 2-phenyl substituent showed a very good affinity and selectivity for the A3 subtype, revealing the first class of A3 adenosine receptor selective antagonists with a bicyclic structure strictly correlated to the adenine nucleus. The molecular modelling work, carried out using the DOCK program, supplied two models which may be useful for a better understanding of the binding modes. Both models highlighted the preferred interacting tautomeric forms of the antagonists for human A1 and A3 receptors.
Biagi
Giuliana
G
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Bianucci
Anna Maria
AM
Coi
Alessio
A
Costa
Barbara
B
Fabbrini
Laura
L
Giorgi
Irene
I
Livi
Oreste
O
Micco
Iolanda
I
Pacchini
Federica
F
Santini
Edoardo
E
Leonardi
Michele
M
Nofal
Fatena Ahmad
FA
Salerni
Oreste LeRoy
OL
Scartoni
Valerio
V
D000225:Adenine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists; D000595:Amino Acid Sequence; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007536:Isomerism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D058918:Adenosine A3 Receptor Antagonists; D001372:Aza Compounds; D008024:Ligands; D043684:Receptor, Adenosine A3; D000225:Adenine