ANALYSIS OF STRUCTURAL REQUIREMENTS FOR AH RECEPTOR ANTAGONIST ACTIVITY - ELLIPTICINES, FLAVONES, AND RELATED-COMPOUNDS

A number of studies have examined the structure-activity relationships for the agonist activity of Ah receptor (AhR) ligands. Fewer studies have considered the structural basis for potential antagonist properti es. Certain ellipticine derivatives have been reported to bind to the AhR and inhibit the ability of 2,3,7,8-tetrachlorodibenzo-9-dioxin (TC DD) to transform the AhR to a form that recognizes a dioxin-responsive enhancer element (DRE) upstream of the cytochrome P4501A1 gene. In th e present study, over 30 ellipticine derivatives and structurally rela ted compounds were examined for their ability to bind to the AhR, acti vate it to a DRE-binding form, induce the luciferase gene under contro l of a DRE-containing enhancer, and block activation of the AhR by TCD D. The ability of several ellipticine derivatives to inhibit TCDD-elic ited DRE binding and TCDD-induced luciferase activity was inversely re lated to their ability to alone stimulate these responses. The most po tent antagonist activity was related to good AhR binding characteristi cs in terms of conforming to previously predicted 14 x 12 x 5 Angstrom van der Waals dimensions and the presence of an electron-rich ring ni trogen at or near a relatively unsubstituted X-axis terminal position. Based on these data, a number of flavone derivatives were synthesized and tested for their relative agonist/antagonist activity. These addi tional data were consistent with the hypothesis that an electron-rich center near or along a lateral position of the van der Waals binding c avity is a characteristic that enhances AhR antagonist activity. Copyr ight (C) 1996 Elsevier Science Inc.