[Hormones and antihormones. The steroidal model]

Area of Science:

• Endocrinology
• Molecular Pharmacology
• Steroid Chemistry

Context:

• Antiglucocorticoids are less clinically used than other antisteroids but are extensively studied.
• The glucocorticoid receptor is a valuable experimental model due to its presence in many cell types.

Purpose:

• To describe the structure-activity relationships of 17 beta-carboxamide derivatives of dexamethasone.
• To investigate how modifications in the 17 beta-side chain affect affinity for the glucocorticoid receptor.

Summary:

• The affinity of dexamethasone 17 beta-carboxamide derivatives for the glucocorticoid receptor is influenced by the 17 beta-side chain substituent, with aromatic groups yielding maximal affinity.
• Antiglucocorticoid activity appears correlated with high dissociation rates, suggesting limited potential for highly active compounds in this series.
• These derivatives, like other antiglucocorticoids, stabilize a high molecular weight form of the receptor associated with HSP90 in intact cells.

Impact:

• Provides insights into the molecular mechanisms of antiglucocorticoid action.
• Informs the design of novel steroid receptor modulators.
• Highlights the role of HSP90 in receptor complex stabilization.