title: 2,9-disubstituted-N6-(arylcarbamoyl)-8-azaadenines as new selective A3 adenosine receptor antagonists: synthesis, biochemical and molecular modelling studies.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Biagi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Bianucci
authors.forename: Alessio
authors.initials: A
authors.lastname: Coi
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Laura
authors.initials: L
authors.lastname: Fabbrini
authors.forename: Irene
authors.initials: I
authors.lastname: Giorgi
authors.forename: Oreste
authors.initials: O
authors.lastname: Livi
authors.forename: Iolanda
authors.initials: I
authors.lastname: Micco
authors.forename: Federica
authors.initials: F
authors.lastname: Pacchini
authors.forename: Edoardo
authors.initials: E
authors.lastname: Santini
authors.forename: Michele
authors.initials: M
authors.lastname: Leonardi
authors.forename: Fatena Ahmad
authors.initials: FA
authors.lastname: Nofal
authors.forename: Oreste LeRoy
authors.initials: OL
authors.lastname: Salerni
authors.forename: Valerio
authors.initials: V
authors.lastname: Scartoni
mesh_terms: 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
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D001372:Aza Compounds; D008024:Ligands; D043684:Receptor, Adenosine A3; D000225:Adenine