Medicinal Chemistry of Adrenocorticoids: HPA-axis Targeting Steroid Drugs Quiz

Steroid Drugs Targeting the HPA-axis

• The Hypothalamic-Pituitary-Adrenal (HPA) axis regulates the body's response to stress, involving the hypothalamus, pituitary gland, and adrenal cortex.
• The HPA axis produces hormones such as corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and hydrocortisone (cortisol).

Glucocorticoid Neuroendocrinology

• Glucocorticoids have pleiotropic effects, including anti-inflammatory, immunosuppressive, gluconeogenic, lipolytic, and catabolic actions.
• Glucocorticoids can also cause hypertension and euphoria.

Adrenocorticoid Signaling

• The glucocorticoid receptor (GR) has a DNA-binding domain with zinc fingers, and is bound to heat shock protein 90 (Hsp90).
• Corticosteroid-binding globulin (CBG) binds to glucocorticoids in the bloodstream.

Targeting Inflammatory Mediators

• Glucocorticoids inhibit the action of phospholipase A2, reducing the production of pro-inflammatory eicosanoids.
• Lipocortin, a glucocorticoid-induced protein, inhibits phospholipase A2.

Glucocorticoids as Immunosuppressive Drugs

• Glucocorticoids suppress the immune system by inhibiting T-cell activation and proliferation.
• Glucocorticoids are often used in combination with other immunosuppressive drugs, such as cyclosporine, azathioprine, and mycophenolate.

Therapeutic Indications for Glucocorticoids

• Glucocorticoids are used to treat inflammatory and immune-related disorders, such as asthma, rheumatoid arthritis, and lupus.

Optimization of Steroid Drugs

• Medicinal chemistry can optimize the potency, specificity, and bioavailability of steroid drugs, such as hydrocortisone (cortisol).
• Substituents involved in cortisol activity can be modified to improve its effects.

Natural and Synthetic Corticosteroids

• Natural corticosteroids, such as cortisol, can be modified to create synthetic corticosteroids with improved potency and specificity.
• Examples of synthetic corticosteroids include prednisone and triamcinolone.

Adrenocorticoid Interconversion and Deactivation

• Corticosteroids can be interconverted between active and inactive forms, affecting their potency and duration of action.

Adrenocorticoid SAR

• The structure-activity relationship (SAR) of adrenocorticoids can be modified to improve their potency, specificity, and metabolic stability.

1-Dehydroderivatives

• 1-Dehydroderivatives of corticosteroids, such as prednisone, can exhibit increased anti-inflammatory activity and improved metabolic stability.

Triamcinolone

• Triamcinolone is an intermediate-acting glucocorticoid with a fluoro substituent, which increases its potency and duration of action.
• D-ring substituents in triamcinolone can prolong its duration of action.