FLAVONOID DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS - A COMPARISON OF THE HYPOTHETICAL RECEPTOR-BINDING SITE BASED ON A COMPARATIVE MOLECULAR-FIELD ANALYSIS MODEL

Flavonoid derivatives have been optimized as relatively rigid antagoni sts of adenosine receptors with particular selectivity for the A(3) re ceptor subtype. A quantitative study of the structure-activity relatio nships for binding of flavonoids to adenosine A(1), A(2A), and A(3) re ceptors has been conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r(2)) of 0.605, 0.5 95, and 0.583 were obtained for the three subtypes, respectively. All three CoMFA models have the same steric and electrostatic contribution s, implying similar requirements inside the binding cavity. Similariti es were seen in the topology of steric and electrostatic regions with the A(1) and A(3) receptors, but not the A(2A). Substitutions on the p henyl ring at the C-2 position of the chromone moiety may be considere d important for binding affinity at all adenosine receptors. In the A( 3) 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 t he chromone moiety is well tolerated and increases the A(1)/A(3) selec tivity. The CoMFA coefficient contour plots provide a self-consistent picture of the main chemical features responsible for the pK(i) variat ions and also result in predictions which agree with experimental valu es.