Glucocorticoids: binding affinity and lipophilicity

The relative binding affinity of 35 steroids for the glucocorticoid receptor was determined in experiments in which the competition of various unlabeled steroids with either [6,7-3H]dexamethasone or [1,2-3H]hydrocortisone for the cytosolic glucocorticoid receptor of cultured human keratinocytes was measured. The data obtained were correlated with steroid lipophilicity, measured as the partition coefficient of the steroid between 1-octanol and pH 7.4 aqueous buffer. The introduction of various substituents on the steroid molecule induced changes in the binding affinity and was associated in some cases with concomitant changes in steroid lipophilicity. The substitution by a 17 alpha-OH or 21-OH group leads in all cases to a decrease in steroid lipophilicity and to an increase in affinity. In contrast, 17 alpha-OAc and especially 21-OAc substitution on hydrocortisone and betamethasone causes a decrease in the steroid affinity for the receptor and an increase in steroid lipophilicity. The elongation of the ester chain from acetate to valerate in both position C-17 and C-21 leads to the increase in both the binding affinity for the receptor and the lipophilicity of steroids. However, all 21-esters showed lower binding affinity than the parent alcohol. The binding affinity of the highly lipophilic 17 alpha, 21-diester was found to be lower than that of the 17 alpha-ester but higher than that of the 21-ester or of the parent alcohol. Only in the series of 17 alpha- and 21-esters is there a correlation between the binding affinity of steroids for the glucocorticoid receptor and their lipophilicity.