沈阳药科大学：《药物化学》课程教学资源（PPT课件讲稿）肾上腺皮质激素 Adrenal Corticoids

Adrenal corticoids 沈阳药科大学 药物化学教研室

沈阳药科大学 药物化学教研室 Adrenal Corticoids

Learning Objectives Gain an understanding of 1. Adrenocorticoids affect both carbohydrate metabolism glucocorticoids) and modulate water balance and Na*/K transport(mineralocorticoid) 2. The nature of the stress activated pathways that control adrenocorticoid secretion 3. Structures of the major mineralo-and glucocorticoids 4. Biosynthesis of mineralo-and glucocorticoids 5. Anti-inflammatory effects of glucocorticoids and the use of pharmacological doses for treatment of inflammation 6 Structure-activity relationships for glucocorticoid activity 7. Development of synthetic glucocorticoids with reduced mineralocorticoid activity 8. Toxicity of adrenal corticoids

Learning Objectives Gain an understanding of: 1. Adrenocorticoids affect both carbohydrate metabolism (glucocorticoids) and modulate water balance and Na+ /K+ transport (mineralocorticoid) 2. The nature of the stress activated pathways that control adrenocorticoid secretion 3. Structures of the major mineralo- and glucocorticoids 4. Biosynthesis of mineralo- and glucocorticoids 5. Anti-inflammatory effects of glucocorticoids and the use of pharmacological doses for treatment of inflammation 6 Structure-activity relationships for glucocorticoid activity 7. Development of synthetic glucocorticoids with reduced mineralocorticoid activity 8. Toxicity of adrenal corticoids

ADRENAL CORTICOIDS 1563 Existence of adrenal gland discovered by Eustachio 1849 Addison attributed "bronzed skin disease to malfunctioning Adrenal glands 1856 Brown-Sequard removed adrenals of cats and dogs who promptly died proving properly functioning adrenals essential for survival 1894 Adrenal divided into medulla secreting adrenaline and the cortex 1938 Reichstein isolates 29 new substances from adrenal cortex all are steroids 1948 Kendall isolates pure cortisone 1950 Kendall, Reichstein and Hench awarded Nobel prize for medicine

ADRENAL CORTICOIDS 1563 Existence of adrenal gland discovered by Eustachio 1849 Addison attributed “bronzed skin” disease to malfunctioning Adrenal glands 1856 Brown-Sequard removed adrenals of cats and dogs who promptly died proving properly functioning adrenals essential for survival 1894 Adrenal divided into medulla secreting adrenaline and the cortex. 1938 Reichstein isolates 29 new substances from adrenal cortex all are steroids 1948 Kendall isolates pure cortisone 1950 Kendall, Reichstein and Hench awarded Nobel prize for medicine

HUMAN ORGANS OF THE ENDOCRINE SYSTEM pineal hypothalmus Steroid hormones are synthesised pituitary Primarily in parathyroid thyroid Adrenal Cortex- Adrenocorticoids thymus Ovaries, testes- Sex steroids g stomachs adrena Steroid secretion is generally controlled by peptides secreted from the pancreas duodenum Hypothalmus and pituitary ovary uterus teste

HUMAN ORGANS OF THE ENDOCRINE SYSTEM pineal hypothalmus pituitary parathyroid thyroid thymus stomach adrenal kidney pancreas ovary uterus testes duodenum Steroid hormones are synthesised primarily in Adrenal Cortex - Adrenocorticoids Ovaries , testes - Sex steroids Steroid secretion is generally controlled by peptides secreted from the: Hypothalmus and pituitary

BIOLOGICAL EFFECTS OF ADRENOCORTICOIDS Modulation of carbohydrate metabolism -Glucocorticoids increases levels of glycogen in the liver and circulating glucose early effects stimulate immune system prolonged secretion leads to immune suppression and cell death basal rhythmic secretion increased during periods of stress Modulation of water balance, promotion of Nat/K transport -Mineralocorticoids promotes Nat uptake in tubular epithelial cells modulates K+ ion transport control of water reabsorption secreted only during periods of stress Glucocorticoid and mineralocorticoid receptors have been discovered and each class of compound can interact with each receptor Secretion of cortisol during stress is essential for li

BIOLOGICAL EFFECTS OF ADRENOCORTICOIDS Modulation of carbohydrate metabolism - Glucocorticoids increases levels of glycogen in the liver and circulating glucose early effects stimulate immune system prolonged secretion leads to immune suppression and cell death basal rhythmic secretion increased during periods of stress Modulation of water balance, promotion of Na+ / K+ transport - Mineralocorticoids promotes Na+ uptake in tubular epithelial cells modulates K+ ion transport control of water reabsorption secreted only during periods of stress Glucocorticoid and mineralocorticoid receptors have been discovered and each class of compound can interact with each receptor Secretion of cortisol during stress is essential for life

STRESSACTIVATED PATHWAYS Humoral pathway STRESS RAS pathway () Limbic system Visceral brain Norepinephrine Endocrine Neuronal pathway Hypothalmus CRF 41 residues Renin Fight or flight Anterior pituitary ACTH 39 residues Angiotensin i& Adrenal cortex Adrenal cortex cortisol glycogen Aldosterone GR receptor increased Antiinflammatory effects blood+- Sodium uptake cell death pressure

STRESS ACTIVATED PATHWAYS Humoral pathway STRESS Neuronal pathway RAS pathway Limbic system Visceral brain Endocrine Hypothalmus Anterior pituitary Adrenal cortex cortisol (-) (-) (-) CRF 41 residues ACTH 39 residues GR receptor Antiinflammatory effects cell death glycogen Fight or flight Norepinephrine Renin Angiotensin I & II Adrenal cortex Aldosterone Sodium uptake increased blood pressure

MAJOR NATURAL GLUCOCORTICOIDS OH OH HO OH HO Cortisol(hydrocortisone OH Corticosterone OH Cortisone

MAJOR NATURAL GLUCOCORTICOIDS Cortisol (hydrocortisone) O OH O HO OH Corticosterone O OH O HO O OH O O OH Cortisone

BIOSYNTHESIS OF GLUCOCORTICOIDS HO OH HO holesterol 17a-hydroxy 11B, 17a(oH)2-progesterone pregnenolone e b OH HOCH2 o HOCH2 O OH OH Ho OH c d HO pregnenolone 17a-hydroxy 11-deoxycortisol 0 Cortisol b. 17a-hydroxylase progesterone e OH 5ene-3β- hydroxy dehydrogenase o C, d d. 3-0X0-45-isomerase OH HOCH2 -O e. 21-hydroxylase OH f. 11B-hydroxylase HO 17x,21(0H)2 pregnenolone Cortisone

BIOSYNTHESIS OF GLUCOCORTICOIDS HO HO O HO O OH O O OH O HOCH2 O OH O HOCH2 O HO OH O HOCH2 O O OH O O HO OH cholesterol pregnenolone 17a-hydroxy￾pregnenolone 17a-hydroxy￾progesterone 11-deoxycortisol Cortisol Cortisone 17a,21(OH)2 - pregnenolone 11b,17a(OH)2 -progesterone OH HO OH O b c,d e f e c,d f e b. 17a-hydroxylase c. 5-ene-3b-hydroxy dehydrogenase d. 3-oxo-4,5-isomerase e. 21-hydroxylase f. 11b-hydroxylase

GLUCOCORTICOID-METABOLISM OH OH Hyo drocortisone Oxidation HO OH OH Cortisone Oxidation/reduction Reduction OH COOH HO OH HO OH OH HO HO H 3-keto-A4 and 20-keto reduced Acid metabolites

GLUCOCORTICOID - METABOLISM O HO O OH OH O O O OH OH Cortisone Hydrocortisone Oxidation Reduction OH H OH HO HO HO H 3-keto-D4 and 20-keto reduced COOH OH OH H HO HO H Oxidation/reduction Acid metabolites

MAJOR NATURAL MINERALOCORTICOIDS HOH2C CH?OH O=CH FO HO Aldosterone desoxycorticosterone

MAJOR NATURAL MINERALOCORTICOIDS HOH2C O CH O HO O Aldosterone CH2OH O O desoxycorticosterone