Competitive binding of 7-substituted-2,3-dichlorodibenzo-p-dioxins with human placental ah receptor--a QSAR analysis

The competitive binding affinities of thirteen 7-substituted-2,3-dichlorodibenzo-p-dioxins to the human placental cytosolic aryl hydrocarbon (Ah) receptor were determined using [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin as the radioligand. Multiple parameter linear regression analysis of the competitive binding C50 values for these compounds gave the following equation: pEC50 (M) = 6.246 + 1.632 pi - 1.764 sigma 0m + 1.282 HB where pi, sigma m and HB are the physiochemical parameters for substituent lipophilicity, meta-directing electronegativity, and hydrogen bonding capacity respectively. The 7-t-butyl- and 7-phenyl-2,3-dichlorodibenzo-p-dioxins were treated as outliers for the derivation of this equation, and these results suggest that only substituents with van der Waals' volumes less than 40 cm3/mol were accommodated in the receptor binding site. The equations previously derived from the binding of the 7-substituted-2,3-dichlorodibenzo-p-dioxins to the rat, mouse, guinea pig, and hamster hepatic cytosolic receptor were different than the correlation obtained using human placental receptor and provide further evidence for the interspecies differences in the molecular and binding properties of the Ah receptor protein.