Binding of substituted aryl hydrocarbons to the Ah receptor - a QAAR analysis

The competitive receptor binding affinities of 13 2-substituted 3,7,8-trichlorodibenzo-p-dioxin (TrCDD) for the rat hepatic cytosolic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor protein was determined using [³H]-2,3,7,8-TCDD as the radioligand. The 2-CF₃ substituted analog was the most active compound in this series (pEC₅₀=8.50) and exhibited a higher binding affinity for the receptor than 2,3,7,8-TCDD. Multiple parameters linear regression analysis of the data gave Equation 1 which correlates binding affinities with the physiochemical characteristics of the substituents. In this equation π, ΔE_S and HB represent pEC₅₀ (rat) = 7.196 + 0.600π - 0.255_δE_s + 1.683 HB (1) (0.140) (0.231) (0.181) (0.267) n = 11 s = 0.099 r = 0.998. substituent lipophilicity, van der Waals volume and hydrogen bonding capacity respectively, n is the number of substituents, s is the standard deviation and r is the correlation coefficient. The effects of substituents on the biologic (aryl hydrocarbon hydroxylase induction) and toxic (thymic atrophy and body weight loss) effects of these compounds was also determined in the immature male Wistar rat. The 2-halo substituted analogs (F, Cl, Br and I) were all highly toxic however the most active compound, 2-trifluoromethyl-3,7,8-trichlorodibenzo-p-dioxin, also exhibited the highest binding affinity for the receptor protein.