Flavonoid derivatives as adenosine receptor antagonists: a comparison of the hypothetical receptor binding site based on a comparative molecular field analysis model

Journal of Medicinal Chemistry
S MoroK A Jacobson

Abstract

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 r2) 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 pKi variations and al...Continue Reading

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Citations

May 17, 2008·Journal of Computer-aided Molecular Design·Stefano CostanziKenneth A Jacobson
Nov 28, 2002·Pharmacology & Therapeutics·Bent H Havsteen
Oct 24, 2002·Neurobiology of Aging·Hagen SchroeterCatherine Rice-Evans
May 30, 2002·Biological Chemistry·Kuresh A YoudimCatherine Rice-Evans
Oct 16, 2014·BMC Complementary and Alternative Medicine·Himangsu MondalShaikh J Uddin
Aug 12, 2015·Neurochemistry International·Catarina RendeiroJeremy P E Spencer
Sep 4, 2010·Journal of Clinical Psychopharmacology·Craig A OlsonHarris R Lieberman
Aug 2, 2007·Medicinal Research Reviews·Maykel Pérez GonzálezMarta Teijeira
Dec 29, 2005·Medicinal Research Reviews·Stefano MoroGiampiero Spalluto
Feb 2, 1999·Journal of Nursing Care Quality·K Malloch
Apr 25, 2013·Chemistry : a European Journal·Priyankar PairaGiorgia Pastorin
Mar 21, 2000·Medicinal Research Reviews·P G BaraldiG Spalluto
Oct 25, 2020·The European Journal of Neuroscience·Giovanni AnnonaMarina Paolucci
Jul 20, 2007·Bioorganic & Medicinal Chemistry·Sheldon HolderMilton L Brown

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