Synthesis and Evaluation of a New Series of 8‐(2‐Nitroaryl)Xanthines as Adenosine Receptor Ligands. Issue 5 (12th July 2016)

• Record Type: Journal Article
• Authors: Bansal, Ranju; Kumar, Gulshan; Rohilla, Suman; Klotz, Karl‐Norbert; Kachler, Sonja; Young, Louise C.; Harvey, Alan L.
• Is Part Of: Drug development research. Volume 77:Issue 5(2016)
• Page Start: 241
• Page End: 250
• Publication Date: 2016-07-12
• Subjects: nitroxanthines -- adenosine receptors -- nitrate esters; Drug development -- Periodicals; Drugs -- Research -- Periodicals; 615.19
• DOI: 10.1002/ddr.21317
• Languages: English
• ISSNs: 0272-4391

Abstract

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.