title: Synthesis and Evaluation of a New Series of 8-(2-Nitroaryl)Xanthines as Adenosine Receptor Ligands.
abstract: Preclinical Research A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds. 8-(4-Cyclopentyloxy-5-methoxy-2-nitrophenyl)-1,3-dimethylxanthine (9e) proved to be a potent compound among the 2-nitrophenyl substituted xanthines exhibiting a Ki  = 1 μM at human A2A ARs with at least 30 fold selectivity versus human A1 and A2B ARs. Replacement of 8-chloropropoxy phenyl with 8-nitrooxypropoxy phenyl resulted in a negligible change in binding affinity of the 8-substituted xanthines for various AR subtypes. Drug Dev Res 77 : 241-250, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
authors.forename: Ranju
authors.initials: R
authors.lastname: Bansal
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
authors.forename: Gulshan
authors.initials: G
authors.lastname: Kumar
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Rohilla
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Würzburg, Wurzburg, Germany.
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Würzburg, Wurzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, United Kingdom.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Young
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, United Kingdom.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Harvey
mesh_terms: D006801:Humans; D008024:Ligands; D011485:Protein Binding; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D014970:Xanthines
keywords: adenosine receptors; nitrate esters; nitroxanthines