EFFECTS OF SUBSTITUENTS ON THE CYTOSOLIC RECEPTOR-BINDING AVIDITIES AND ARYL-HYDROCARBON HYDROXYLASE INDUCTION POTENCIES OF 7-SUBSTITUTED 2,3-DICHLORODIBENZO-PARA-DIOXINS - A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 27  (6) , 656-661
Abstract
The binding affinities of sixteen 7-substituted 2,3-dichlorodibenzo-p-dioxins for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cytosolic receptor protein from male Wistar rats were determined. The EC50 value for each compound was estimated by competitive displacement of [3H]TCDD and the data illustrated that the differences between competitive ligands were dependent on the substituent (X) group. The EC50 value for 7-trifluoromethyl-2,3-dichlorodibenzo-p-dioxin was 1.95 .times. 10-8 M and was > 1000-fold more active than 7-amino-2,3-dichlorodibenzo-p-dioxin (EC50 = 2.88 .times. 10-5 M). Multiple parameter linear regression analysis of the data for 14 different compounds gave the following equation: log (1/EC50) = 1.24.pi. + 6.11. This demonstrated that the binding affinity was linearly dependent on the lipophilicity (.pi.) of the 7-X-group. This contrasted with a comparable analysis of the substituent effects on the binding of thirteen 4''-substituted 2,3,4,5-tetrachlorobiphenyls to the cytosolic receptor which showed that the lipophilicity, electronegativity and hydrogen-bonding capacity were important physicochemical determinants which facilitated binding to the receptor protein. These data suggest that the halogenated dibenzo-p-dioxins and biphenyls may interact with different binding sites on the receptor or they may bind to the same site, but exert different conformational effects on the receptor protein. For the 7-X-2,3-,-dichlorodibenzo-p-dioxins, there was not a rank order correlation between receptor-binding EC50 values, and the induction of aryl hydrocarbon hydroxylase (AHH) or ethoxyresorufin O-deethylase in rat hepatoma H-4-II E cells in culture. However, the data could be correlated with an estimate of substituent width, the Sterimol factor (B5), i.e., log (AHH) = 1.29 log (binding) + 2.19.delta.B5-1.31 (.DELTA.B5)2-1.48. The importance of a steric factor in the correlation between receptor binding and AHH induction for substituted dibenzo-p-dioxins and halogenated biphenyls is consistent with a structure-dependent conformational change(s) in the receptor protein:ligand complex after the initial binding event. Presumably, this latter process is associated with the steps involving interactions between the ligand:receptor complex and nuclear binding sites.

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