New potent and selective A1 adenosine receptor antagonists as potential tools for the treatment of gastrointestinal diseases.

Abstract

The synthesis of 9-alkyl substituted adenine derivatives presenting aromatic groups and cycloalkyl rings in 8- and N6-position, respectively, is reported. The compounds were tested with radioligand binding studies showing, in some cases, a low nanomolar A1 adenosine receptor affinity and a very good selectivity versus the other adenosine receptor subtypes. Functional assays at human adenosine receptors and at a mouse ileum tissue preparation clearly demonstrate the antagonist profile of these molecules, with inhibitory potency at nanomolar level. A molecular modeling study, consisting in docking analysis at the recently reported A1 adenosine receptor crystal structure, was performed for the interpretation of the obtained pharmacological results. The N6-cyclopentyl-9-methyl-8-phenyladenine (17), resulting the most active derivative of the series (Ki = 2.8 nM and IC50 = 14 nM), was also very efficacious in counteracting the effect of the agonist CCPA on mouse ileum contractility. This new compound represents a tool for the development of new agents for the treatment of intestinal diseases as constipation and postoperative ileus.

• Authors: Catia Lambertucci, Gabriella Marucci, Diego Dal Ben, Michela Buccioni, Andrea Spinaci, Sonja Kachler, Karl-Norbert Klotz, Rosaria Volpini
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 151 Pg. 199-213 (May 10 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29614417 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Adenosine A1 Receptor Antagonists
• Receptor, Adenosine A1
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology, therapeutic use)
• Adenosine A1 Receptor Antagonists (chemistry, pharmacology, therapeutic use)
• Animals
• CHO Cells
• Cricetulus
• Gastrointestinal Diseases (drug therapy, metabolism, physiopathology)
• Gastrointestinal Motility (drug effects)
• Humans
• Ileum (drug effects, metabolism, physiopathology)
• Male
• Mice
• Mice, Inbred BALB C
• Molecular Docking Simulation
• Receptor, Adenosine A1 (metabolism)