Flavonoid Derivatives as Adenosine Receptor Antagonists:  A Comparison of the Hypothetical Receptor Binding Site Based on a Comparative Molecular Field Analysis Model

• Published in: Journal of medicinal chemistry 1998-01, Vol.41 (1), p.46-52
• Main Authors: Moro, Stefano, van Rhee, A. Michiel, Sanders, Lawrence H, Jacobson, Kenneth A
• Format: Article
• Language: English
• Subjects: Binding Sites; Biological and medical sciences; Computer Simulation; Flavonoids - chemistry; Flavonoids - pharmacokinetics; Flavonoids - pharmacology; Kinetics; Least-Squares Analysis; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Purinergic P1 Receptor Antagonists; Receptor, Adenosine A3; Receptors, Purinergic P1 - chemistry; Regression Analysis; Reproducibility of Results; Static Electricity; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970446z

Flavonoid derivatives have been optimized as relatively rigid antagonists of adenosine receptors with particular selectivity for the A3 receptor subtype. A quantitative study of the structure-activity relationships for binding of flavonoids to adenosine A1, A2A, and A3 receptors has been conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r 2) of 0.605, 0.595, and 0.583 were obtained for the three subtypes, respectively. All three CoMFA models have the same steric and electrostatic contributions, implying similar requirements inside the binding cavity. Similarities were seen in the topology of steric and electrostatic regions with the A1 and A3 receptors, but not the A2A. Substitutions on the phenyl ring at the C-2 position of the chromone moiety may be considered important for binding affinity at all adenosine receptors. In the A3 model a region of favorable bulk interaction is located around the 2‘-position of the phenyl ring. The presence of a C-6 substituent in the chromone moiety is well tolerated and increases the A1/A3 selectivity. The CoMFA coefficient contour plots provide a self-consistent picture of the main chemical features responsible for the pK i variations and also result in predictions which agree with experimental values.