A new structure-affinity relationship for TCDD receptor binding

We have investigated the capacity of various indoles to inhibit specific binding of 1,6-³H]2,3,7,8-tetrachlorodibenzo- -dioxin (³H]TCDD) in rat liver cytosol, as analyzed by electrofocusing in polyacrylamide gels. Of these indoles, indolo3,2- ]carbazole was the most active. The IC₅₀ value for TCDD receptor binding of indolo3,2- ]carbazole as well as for 2,3,7,8-tetrachlorodibenzofuran was 3.6 nM. We have also studied the influence on binding exerted by introduction of some substituents on indolo3,2- ]carbazole. Substitution with methyl groups at the 5 and 11 positions resulted in an increased affinity (IC₅₀ 1.2 nM) for the TCDD receptor as compared to the parent compound. Computer-supported molecular structure studies indicated that if the van der Waals radii of atoms are included, a rectangle of 6.8 × 13.7 Å may account for the binding of high-affinity ligands to the TCDD receptor.