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
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
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 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
STRESS ACTIVATED PATHWAYS
Humoral pathway STRESS
Neuronal pathway
RAS pathway
Visceral brainLimbic system
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
Cortisol (hydrocortisone)
O
O H
O
O HH O
Corticosterone
O
O H
O
H O
O
O H
O
O O H
Cortisone
BIOSYNTHESIS OF GLUCOCORTICOIDS RT
HO
HO
O
HO
O
OH
O
O
OH
O
HOCH2 O
OH
O
HOCH2 O
OHHO
O
HOCH2 O
OHO
O
O
OHHO
cholesterol
pregnenolone
17a-hydroxy-
pregnenolone
17a-hydroxy-
progesterone
11-deoxycortisol Cortisol
Cortisone
17a,21(OH)2-
pregnenolone
11b,17a(OH)2-progesterone
O H
H O
O H
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
O
H O
O
O H
O H
O
O
O
O H
O H
Cortisone
Hydrocortisone Oxidation
Reduction
O H
H
O H
H O
H O
H O
H
3-keto-D4 and 20-keto reduced
C O O H
O H
O H
H
H O
H O
H
Oxidation/reduction
Acid metabolites
MAJOR NATURAL MINERALOCORTICOIDS
H O H 2 C
O
C H
O
H O
O
Aldosterone
C H 2 O H
O
O
desoxycorticosterone
BIOSYNTHESIS OF MINERALOCORTICOIDS
H O
H O
O
H O C H
2
O
O
O
O
H O C H
2
O
O
H O
O
H O
C
H O C H
2
C H
2
H O
O
O
H O
H O C H
2
C H
O
O
O
H O
C H
2
O H
C H
O
O H
progesterone deoxycortico-
sterone cortico-sterone
18-hydroxy-
corticosterone Aldosterone
Aldosterone
(hemiacetal form)
pregnenolone
c,d
e f g
c,5-ene-3b-hydroxy
dehydrogenase
d,3-oxo-4,5-isomerase
e,21-hydroxylase
f,11b-hydroxylase
g,18-hydroxylase
ANTIINFLAMMATORY EFFECTS OF
GLUCOCORTICOIDS
April,1948 1 Gram cortisone isolated by Kendall
September 21,1948 Hench administers 100mg of cortisone by intra-
muscular injection to patient Mrs,G,suffering chronic Rheumatoid Arthritis
September 28,1948 Mrs,G,first time in years walks downtown to go
shopping,
Represented a new approach to therapy with natural hormones
by utilising a dose much higher than that naturally produced by the body
ie,pharmacological rather than physiological dose.
MODE OF ACTION GLUCOCORTICOIDS IN
PREVENTING INFLAMMATION
Steroid + receptor
Represses
inducible
COX2
Synthesis lipocortin
or annexin 1
Intracellular membrane
phospholipids
Arachidonic acid
prostaglandin
INFLAMMATION
Release into cytosol
or from cell
Phospholipase A2
inhibits
THERAPEUTIC APPLICATION
ADRENOCORTICOIDS
Glucocorticoids
Agonists - adrenal insufficiency
- rheumatoid disease and allergic manifestations
(eg,severe asthma,rheumatoid arthritis,rheumatic fever)
Palliative therapy only not curative
Antagonists - Cushings Syndrome
Mineralocorticoids
Agonists - adrenal insufficiency,generally glucocorticoids used in this
application
Antagonists - Cushings syndrome
- test functioning of hypothalamico-pituitary axis
CORTISONE PREPARATIONS
Cortisone is primarily used as its 21-acetate
because of increased stability and longer
duration of action
O
O
O
O O H
C H 3
O
Other 21-ester derivatives available
include:
O
O
O HH O
O R
C OHydrocortisone cypionate R =
Hydrocortamate sodium succinate
R = Na+ -OOCCH2CH2CO- (water soluble)
Intraveinous emergency treatment
Oral or intramuscular dose usually
25 mg 4 times daily
Topically 1 to 2.5% lotion
RELATIVE POTENCIES OF CORTICOSTEROIDS
Compound Na+ Hepatic Antiinflammatory
retention glycogen effect
deposition
Cortisol 1 1 1
Cortisone 0.8 0.8 0.8
Corticosterone 15 0.35 0.3
11-desoxycortico-
sterone 100 0 0
Aldosterone 3000 0.3?
Most natural or synthetic compounds have some activity at both GR
and MR receptors
STRUCTURE-ACTIVITY GLUCOCORTICOIDS
Large doses of steroids used for treating rheumatoid arthritis resulted in
significant side effects including excessive Na+ retention and K+ excretion
Intensive efforts for compounds with reduced mineralocorticoid activity
Structure-activity for glucocorticoid activity
O
O H
O
H O
H O
Required for activity
3-keto group
4,5-double bond
11- oxygen (keto or alcohol)
17-b ketol sidechain
Synthetic Corticosteroids
O H
O
O H
O
H O
11-epicortisol
9a-bromo analogue
O H
O
O H
O
B r
H O
1/3 activity of cortisone acetate
O H
O
O H
O
F
H O
11 times activity of cortisone acetate
Fludrocortisone
Glucocorticoid activity inversely
Proportional to size of 9a-halogen
SYNTHETIC GLUCOCORTICOIDS
D-corticoids
O
O H
O
H O
H O
O
O H
O
H O
O
Prednisolone
(GR 4 MR unchanged)
Prednisone (GR 4 MR unchanged)
Greater activity allows smaller doses
D-corticoids to be used reducing
side effects
Prednisone and Prednisolone can be used
interchangeably
Rheumatoid arthritis 2-4 mg /day
O
O H
O
H O
C H 3
H O
Methylprednisolone (GR 5 MR unchanged)
Conformational Change in D-Corticoids
O
C H 3
O
C H 3
C H 3
ORing A of
5a-pregnan-3-one
Ring A of pregn-4-en-3-one
Chair
Half-chair
Flattened boat
SYNTHETIC GLUCOCORTICOIDS
O
O H
O
H O
H O
O H
F
O
O H
O
H O
H O
F
O
O
O
H O
H O
F
O
betamethasone GR 35 fold
triamcinolone GR 5 fold triamcinolone acetonide
MR activity
20% more effective than prednisolone
Unusual toxic side effects
Used topically for treatment of
psoriasis and other skin conditions
Rheumatic and dermatologic disorders
Short period use only
Fludrocortisone (GR activity 11)
MR activity 300-800 fold
O H
O
O H
O
F
H O
TOXICITY OF ADRENOCORTICAL STEROIDS
Prolonged use
Primarily results in fluid and electrolyte disturbances
eg,hypertension,hyperglycemia,glycosuria
Increased susceptibility to infection including tuberculosis
Peptic ulcers,osteoporosis,myopathy,central obesity,behavioral
disturbances
Withdrawal effects
Prolonged adrenocorticoid use results in pituitary- adrenal suppresion
This system may take as long as 1 to 2 years to recover
Patients may need supplemental corticosteroids during this period
THERAPEUTIC USE OF CORTICOSTEROIDS
1,Appropriate dose in each case is determined by trial and error
2,Single dose of corticosteroid is virtually without harmful effect
3,A few days of usage is unlikely to produce harmful effects except
at extreme doses.
4,Prolongation of treatment increases the incidence of disabling or
life threatening effects
5,Corticosteroids are neither specific or curative treatment
6,Abrupt cessation of prolonged high dose treatment may induce
adrenal insufficiency serious enough to be life threatening.
ADRENOCORTICOID ANTAGONISTS
O
O
O S
O
C H 3
Spironolactone
Diuretic response of increased Na+ excretion and
K+ retention
O
O O
C H 3
H 3 C O H
C C C H 3
progesterone
mifeprestone
mineralocorticoid antagonist glucocorticoid antagonist
INHIBITORS OF BIOSYNTHESIS OF
CORTICOSTEROIDS
Metyrapone
Ketoconazole
inhibits 3b-hydroxysteroid dehydrogenase
(Cushings Syndrome - currently not recommended)
O
N
N
O H
O
H O
N C
O
O
N
N
H
O
N
N
O
C l
C l
Trilostane
blocks cholesterol sidechain
cleavage in the adrenal
(Cushings Syndrome)
inhibits 11b-hydroxylation
reaction
Used for diagnosis hypothalmus-
pituitary malfunction
Summary
1,Glucocorticoids modulate carbohydrate metabolism ie cortisol,cortisone
2,Mineralocorticoids modulate water balance and Na+/K+ transport
ie aldosterone and desoxycorticosterone
3,Biosynthesis of corticosteroids starts with cholesterol the pregnenolone
then progesterone and then final hormone
4,Antiinflammatory effects of glucocorticoids mediated by inhibition of
phospholipase A2,inducible COX2 and annexin I
5,17-esterification facilitates administration
6,All corticosteroids contain both glucocorticoid and mineralocorticoid
activity
7,SAR for glucocorticoid activity,3-keto,4,5-double bond,11-oxy,17-b ketol
all essential for activity
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
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 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
STRESS ACTIVATED PATHWAYS
Humoral pathway STRESS
Neuronal pathway
RAS pathway
Visceral brainLimbic system
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
Cortisol (hydrocortisone)
O
O H
O
O HH O
Corticosterone
O
O H
O
H O
O
O H
O
O O H
Cortisone
BIOSYNTHESIS OF GLUCOCORTICOIDS RT
HO
HO
O
HO
O
OH
O
O
OH
O
HOCH2 O
OH
O
HOCH2 O
OHHO
O
HOCH2 O
OHO
O
O
OHHO
cholesterol
pregnenolone
17a-hydroxy-
pregnenolone
17a-hydroxy-
progesterone
11-deoxycortisol Cortisol
Cortisone
17a,21(OH)2-
pregnenolone
11b,17a(OH)2-progesterone
O H
H O
O H
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
O
H O
O
O H
O H
O
O
O
O H
O H
Cortisone
Hydrocortisone Oxidation
Reduction
O H
H
O H
H O
H O
H O
H
3-keto-D4 and 20-keto reduced
C O O H
O H
O H
H
H O
H O
H
Oxidation/reduction
Acid metabolites
MAJOR NATURAL MINERALOCORTICOIDS
H O H 2 C
O
C H
O
H O
O
Aldosterone
C H 2 O H
O
O
desoxycorticosterone
BIOSYNTHESIS OF MINERALOCORTICOIDS
H O
H O
O
H O C H
2
O
O
O
O
H O C H
2
O
O
H O
O
H O
C
H O C H
2
C H
2
H O
O
O
H O
H O C H
2
C H
O
O
O
H O
C H
2
O H
C H
O
O H
progesterone deoxycortico-
sterone cortico-sterone
18-hydroxy-
corticosterone Aldosterone
Aldosterone
(hemiacetal form)
pregnenolone
c,d
e f g
c,5-ene-3b-hydroxy
dehydrogenase
d,3-oxo-4,5-isomerase
e,21-hydroxylase
f,11b-hydroxylase
g,18-hydroxylase
ANTIINFLAMMATORY EFFECTS OF
GLUCOCORTICOIDS
April,1948 1 Gram cortisone isolated by Kendall
September 21,1948 Hench administers 100mg of cortisone by intra-
muscular injection to patient Mrs,G,suffering chronic Rheumatoid Arthritis
September 28,1948 Mrs,G,first time in years walks downtown to go
shopping,
Represented a new approach to therapy with natural hormones
by utilising a dose much higher than that naturally produced by the body
ie,pharmacological rather than physiological dose.
MODE OF ACTION GLUCOCORTICOIDS IN
PREVENTING INFLAMMATION
Steroid + receptor
Represses
inducible
COX2
Synthesis lipocortin
or annexin 1
Intracellular membrane
phospholipids
Arachidonic acid
prostaglandin
INFLAMMATION
Release into cytosol
or from cell
Phospholipase A2
inhibits
THERAPEUTIC APPLICATION
ADRENOCORTICOIDS
Glucocorticoids
Agonists - adrenal insufficiency
- rheumatoid disease and allergic manifestations
(eg,severe asthma,rheumatoid arthritis,rheumatic fever)
Palliative therapy only not curative
Antagonists - Cushings Syndrome
Mineralocorticoids
Agonists - adrenal insufficiency,generally glucocorticoids used in this
application
Antagonists - Cushings syndrome
- test functioning of hypothalamico-pituitary axis
CORTISONE PREPARATIONS
Cortisone is primarily used as its 21-acetate
because of increased stability and longer
duration of action
O
O
O
O O H
C H 3
O
Other 21-ester derivatives available
include:
O
O
O HH O
O R
C OHydrocortisone cypionate R =
Hydrocortamate sodium succinate
R = Na+ -OOCCH2CH2CO- (water soluble)
Intraveinous emergency treatment
Oral or intramuscular dose usually
25 mg 4 times daily
Topically 1 to 2.5% lotion
RELATIVE POTENCIES OF CORTICOSTEROIDS
Compound Na+ Hepatic Antiinflammatory
retention glycogen effect
deposition
Cortisol 1 1 1
Cortisone 0.8 0.8 0.8
Corticosterone 15 0.35 0.3
11-desoxycortico-
sterone 100 0 0
Aldosterone 3000 0.3?
Most natural or synthetic compounds have some activity at both GR
and MR receptors
STRUCTURE-ACTIVITY GLUCOCORTICOIDS
Large doses of steroids used for treating rheumatoid arthritis resulted in
significant side effects including excessive Na+ retention and K+ excretion
Intensive efforts for compounds with reduced mineralocorticoid activity
Structure-activity for glucocorticoid activity
O
O H
O
H O
H O
Required for activity
3-keto group
4,5-double bond
11- oxygen (keto or alcohol)
17-b ketol sidechain
Synthetic Corticosteroids
O H
O
O H
O
H O
11-epicortisol
9a-bromo analogue
O H
O
O H
O
B r
H O
1/3 activity of cortisone acetate
O H
O
O H
O
F
H O
11 times activity of cortisone acetate
Fludrocortisone
Glucocorticoid activity inversely
Proportional to size of 9a-halogen
SYNTHETIC GLUCOCORTICOIDS
D-corticoids
O
O H
O
H O
H O
O
O H
O
H O
O
Prednisolone
(GR 4 MR unchanged)
Prednisone (GR 4 MR unchanged)
Greater activity allows smaller doses
D-corticoids to be used reducing
side effects
Prednisone and Prednisolone can be used
interchangeably
Rheumatoid arthritis 2-4 mg /day
O
O H
O
H O
C H 3
H O
Methylprednisolone (GR 5 MR unchanged)
Conformational Change in D-Corticoids
O
C H 3
O
C H 3
C H 3
ORing A of
5a-pregnan-3-one
Ring A of pregn-4-en-3-one
Chair
Half-chair
Flattened boat
SYNTHETIC GLUCOCORTICOIDS
O
O H
O
H O
H O
O H
F
O
O H
O
H O
H O
F
O
O
O
H O
H O
F
O
betamethasone GR 35 fold
triamcinolone GR 5 fold triamcinolone acetonide
MR activity
20% more effective than prednisolone
Unusual toxic side effects
Used topically for treatment of
psoriasis and other skin conditions
Rheumatic and dermatologic disorders
Short period use only
Fludrocortisone (GR activity 11)
MR activity 300-800 fold
O H
O
O H
O
F
H O
TOXICITY OF ADRENOCORTICAL STEROIDS
Prolonged use
Primarily results in fluid and electrolyte disturbances
eg,hypertension,hyperglycemia,glycosuria
Increased susceptibility to infection including tuberculosis
Peptic ulcers,osteoporosis,myopathy,central obesity,behavioral
disturbances
Withdrawal effects
Prolonged adrenocorticoid use results in pituitary- adrenal suppresion
This system may take as long as 1 to 2 years to recover
Patients may need supplemental corticosteroids during this period
THERAPEUTIC USE OF CORTICOSTEROIDS
1,Appropriate dose in each case is determined by trial and error
2,Single dose of corticosteroid is virtually without harmful effect
3,A few days of usage is unlikely to produce harmful effects except
at extreme doses.
4,Prolongation of treatment increases the incidence of disabling or
life threatening effects
5,Corticosteroids are neither specific or curative treatment
6,Abrupt cessation of prolonged high dose treatment may induce
adrenal insufficiency serious enough to be life threatening.
ADRENOCORTICOID ANTAGONISTS
O
O
O S
O
C H 3
Spironolactone
Diuretic response of increased Na+ excretion and
K+ retention
O
O O
C H 3
H 3 C O H
C C C H 3
progesterone
mifeprestone
mineralocorticoid antagonist glucocorticoid antagonist
INHIBITORS OF BIOSYNTHESIS OF
CORTICOSTEROIDS
Metyrapone
Ketoconazole
inhibits 3b-hydroxysteroid dehydrogenase
(Cushings Syndrome - currently not recommended)
O
N
N
O H
O
H O
N C
O
O
N
N
H
O
N
N
O
C l
C l
Trilostane
blocks cholesterol sidechain
cleavage in the adrenal
(Cushings Syndrome)
inhibits 11b-hydroxylation
reaction
Used for diagnosis hypothalmus-
pituitary malfunction
Summary
1,Glucocorticoids modulate carbohydrate metabolism ie cortisol,cortisone
2,Mineralocorticoids modulate water balance and Na+/K+ transport
ie aldosterone and desoxycorticosterone
3,Biosynthesis of corticosteroids starts with cholesterol the pregnenolone
then progesterone and then final hormone
4,Antiinflammatory effects of glucocorticoids mediated by inhibition of
phospholipase A2,inducible COX2 and annexin I
5,17-esterification facilitates administration
6,All corticosteroids contain both glucocorticoid and mineralocorticoid
activity
7,SAR for glucocorticoid activity,3-keto,4,5-double bond,11-oxy,17-b ketol
all essential for activity
