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 properties. Certain ellipticine derivatives have been reported to bind to the AhR and inhibit the ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to transform the AhR to a form that recognizes a dioxin-responsive enhancer element (DRE) upstream of the cytochrome P4501A1 gene. In the present study, over 30 ellipticine derivatives and structurally related compounds were examined for their ability to bind to the AhR, activate it to a DRE-binding form, induce the luciferase gene under control of a DRE-containing enhancer, and block activation of the AhR by TCDD. The ability of several ellipticine derivatives to inhibit TCDD-elicited DRE binding and TCDD-induced luciferase activity was inversely related to their ability to alone stimulate these responses. The most potent antagonist activity was related to good AhR binding characteristics in terms of conforming to previously predicted 14 x 12 x 5 A van der Waals dimensions and the presence of an electron-rich ring nitrogen 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 additional data were consistent with the hypothesis that an electron-rich center near or along a lateral position of the van der Waals binding cavity is a characteristic that enhances AhR antagonist activity.