Pharmaceutical Chemistry II Steroids Joseph O. Oweta | PHC 3201

Objectives Gestogens Bile Acids Adrenocorticosteroids

Gestogens Progesterone has significant progestational action…acts via progesterone receptors Progesterone is produced in the: – Testes – Ovaries – Adrenal Glands

Biological Activities Targets: Uterus, Breast & Brain. Brain – Increases Pulse of LH from the pituitary Uterus – Dev’t of 2 o Endometrium. – Thickening cervical secretions Breasts – Preparation for lactation

Structural Classes a)Progesterone and derivatives b)Testosterone and 19-nortestosterone derivatives c)Misc. Progestins

SAR’s The progesterone 4-en-3-one ring A is important for binding only if the molecular config. is different from testosterone or the glucocorticoids (Duax and Co workers) 19-norprogesterone maintains good progestational activity. – Still have androgenic activity – Primary effect is progestational activity 17α-alkynyl testosterone(Ethisterone) has greater progestational activity than androgenic activity. – 17α-alkynyl group blocks met. of the 17-ones – i.e Decreased androgenic activity Promotes good gestational activity Oral activity

Progesterone and Derivatives A Ring Rapid Met. Oral admin Caproate protects 20- one Long acting Adds OH Adds CH 3 Protects A ring Acetate protects 20-one Orally Active ?

Ethisterone Vs. Testosterone Systematic Name?

Levonogestrel Vs. Nortestosterone Systematic name? Nortestosterone Derivative

Pharmaceutical Chemistry II Hormones Joseph O. Oweta | PHC 3201

Objectives Introduction – Adrenal Cortex Hormones – Biological Activities Structural Classes – Mineralocorticoids – Glucocorticoids – Mineralocorticoid Receptor Antagonists

Introduction Adrenal Cortex Hormones Secretes over 50 different steroids Most Significant are: Aldosterone (1 o Mineralocorticoid) Hydrocortisone (1 o Glucocorticoid) Glucocorticoids are important for anti- inflammatory activity Mineralocorticoid receptor antagonists are important diuretics

Aldosterone effects Release leads to increased uptake in distal tubule. Leads to increased blood volume. Also leads to increased K + excretion. Other epithelia include: – Sweat Glands – Small intestine – Salivary Glands & Colon

Glucocorticoids Physiological Functions Influence carbohydrate, protein, lipid and purine metabolism – Induce syn. of glycogen synthase – Induce gluconeogenesis in the liver – Catabolic effect on Muscles. – Increased lipid metabolism Affect CVS, Nervous and Skeletal System – Deficiency associated with Stress Depression Irritability Pyschosis

Anti-inflammatory & immunosuppressive actions. Glucocorticoid-receptor complexes may activate or repress associated genes. – Repression  Antiinflammatory action Inhibit transcription of genes encoding: – Cytokines e.g. Int. ϒ, TNF-α – Interleukins – Gran./Monocyte colony stimulating factor. – Other factors?

Anti-inflammatory & immunosuppressive actions.

Structural Classes Mineralocorticoids Glucocorticoids – Moderate to low salt retention Cortisone Hydrocortisone Their 1-enes Prednisolone Prednisone – Very little or no salt retention See Table

Mineralocorticoids (High Salt Retention) Aldosterone Structure (Discussed)

Glucocorticoids Low – moderate Salt retention 11β-OH - Receptor Binding - Good tropical activity unlike the 11-one 1-ene -X 4 Anti-infl. Activity - Salt Retention (Cortisol) 9 α -Haloderivatives Eln. Withdrawing -> Inc. Acidity of OH ->Better Hydrogen Bonding ->Inc. Potency Reduce oxidation to the One

Further Reading Glucocorticoids with Low – moderate Salt retention (Discussed) – Compare the structures of Cortisone to prednisone Glucocorticoids with very little or no Salt retention – SAR’s and Structures of: Betamethasone Dexamethasone Methyl Prednisolone Make a review of the structure and name of Spironolactone

The End Wrap up seminar tomorrow in Groups