Mifepristone is used for medical abortion but also as a cortisol antagonist in Cushing's syndrome. At the glucocorticoid receptor (GR), mifepristone acts as a:

• A Competitive antagonist that binds GR with high affinity but recruits nuclear co-repressors instead of co-activators, blocking genomic glucocorticoid effects ✓
• B Inverse agonist that reduces basal constitutive GR activity below baseline
• C Partial agonist with 20% intrinsic activity allowing partial cortisol signaling while blocking excess cortisol binding
• D Functional antagonist acting through non-genomic rapid signaling pathways at the plasma membrane

Explanation

Mifepristone (RU-486) binds the glucocorticoid receptor with higher affinity than cortisol. Upon binding, it induces a conformational change in the receptor ligand-binding domain that recruits nuclear co-repressors (e.g., SMRT, NCoR) rather than co-activators, preventing the transcriptional activation normally induced by cortisol. This makes mifepristone a high-affinity competitive antagonist with no intrinsic agonist activity at GR. Its utility in Cushing's syndrome (Korlym) is predicated on this mechanism—it does not reduce cortisol synthesis (ACTH and cortisol levels may even rise) but prevents cortisol from signaling to target tissues. It also antagonizes progesterone receptor, explaining its abortifacient use.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.