Endocrinology, Vol 114, 2252-2263, Copyright © 1984 by Endocrine Society

ARTICLES

Glucocorticoid versus antiglucocorticoid activity: can a single functional group modification of glucocorticoid steroids always convey antiglucocorticoid activity?

N Lamontagne, L Mercier, M Pons, EB Thompson and SS Simons Jr

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 greater than dexamethasone greater than 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 vs. 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 X 10(-8) M. 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.(ABSTRACT TRUNCATED AT 400 WORDS)

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