GlucocorticoidVersusAntiglucocorticoid Activity: Can a Single Functional Group Modification of Glucocorticoid Steroids Always Convey Antiglucocorticoid Activity?

Publisher Website
Google Scholar
Abstract
Single functional group modifications of glucocorticoid steroids have been performed in an effort to obtain antiglucocorticoids with high affinity and specificity for glucocorticoid receptors. This approach tests the hypothesis that the structural determinants of biological activity and receptor binding are independent so that modification of more potent glucocorticoids could yield more potent antiglucocorticoids. In this study, a new functional group capable of conferring antiglucocorticoid activity has been identified, i.e. the spiro C-17 oxetan-3′-one group. Using three glucocorticoids of greatly different potency (deacylcortivazol > dexamethasone > cortisol), we examined the effects of incorporation of the oxetanone group and the previously described, alkylating C-21 mesylate group on steroid affinity for receptors and biological activity. In both series of modified steroids, the receptor affinity of the derivatives paralleled that of the parent steroids. The biological activities of the dexamethasone and cortisol derivatives were predominantly or totally antagonistic, while both deacylcortivazol derivatives were full agonists. We conclude that antiglucocorticoid activity can arise from the incorporation of a single functional group into glucocorticoid steroid structures, but that the expression of agonist us. antagonist activity is determined by a balance of structural group determinants which are not restricted to a common region of the steroid. Within a given class of derivatives, receptor affinity correlated with the amount of agonist activity. The structure-activity relationships for dexamethasone oxetanone and deacylcortivazol mesylate were studied in detail. Dexamethasone oxetanone is a potent antiglucocorticoid in HTC cells. [3H]Dexamethasone oxetanone binds to cell-free glucocorticoid receptors with a Kd of 3.2 × 10−8m. No specific antiglucocorticoid binder was detected. Direct binding experiments with [3H] dexamethasone oxetanone as well as indirect studies of the kinetics of cell-free competition of [3H] dexamethasone binding demonstrated that dexamethasone oxetanone binds to receptors faster (by about a factor of 2) and dissociates from receptors much faster than does dexamethasone. Deacylcortivazol mesylate was a more potent agonist and binder to receptors than dexamethasone, but displayed no irreversible interactions with HTC cell receptors under those conditions that afforded a covalent receptor-steroid complex with the closely related dexamethasone mesylate. Thus, the molecular geometry of receptorbound deacylcortivazol mesylate appears to be different from those of cortisol mesylate and dexamethasone mesylate. These studies further define the structural features involved in steroid binding to glucocorticoid receptors and place limitations on the approaches that can be used to prepare antiglucocorticoid steroids and affinity labels for the glucocorticoid receptor. (Endocrinology114: 2252, 1984)