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Steroid Hormones: Adrenocorticoids (Adrenal Steroids) : A Cap-Like
Steroid Hormones: Adrenocorticoids (Adrenal Steroids) : A Cap-Like
(ADRENAL STEROIDS)
The adrenal gland is a cap-like organ sitting at the upper pole of the
kidney. Histologically, the gland consists of the inner adrenal
medulla and the outer adrenal cortex (shell). In accord with this
histological differentiation, there are two endocrine organs within
the adrenal gland, one surrounding the other. The inner adrenal
medulla secretes the catecholamines: epinephrine and
norepinephrine. The outer adrenal cortex secretes corticosteroid
hormones: glucocorticoids and mineralocorticoids.
1
The adrenal cortex is divided into three zones:
2
Like most endocrine glands, the adrenal cortex is regulated by
hypothalamo-pituitary peptides. The hypothalamus secretes
corticotropin releasing factor (CRF), which controls the release of
adrenocorticotropin (ACTH), a peptide consisting of 39 amino
acids. Corticotropin secretion is under feedback regulation by the
adrenal steroids, as well as being under the control of higher CNS
centers; stress or epinephrine can also increase corticosteroid
production. Adrenocortical secretion is controlled primarily by
ACTH from the anterior pituitary, but mineralocorticoid secretion
is also subject to independent control by circulating factors, of
which the most important is angiotensin II.
3
On the basis of biochemical effects, the two groups of
corticosteroids can be readily distinguished:
4
STEROID HORMONES:
ADRENOCORTICOIDSGLUCOCORTICOIDS
5
Glucocorticoid Receptor
6
Glucocorticoids: StructureActivity Correlations
The structureactivity relationships of glucocorticoids are based on two
natural hormones, cortisol (15.1) and corticosterone (15.2). The
characteristic structural features of these hormones are the conjugated 3-
ketone, the 11-OH group, and the l7 beta-ketol side chain. Molecular
modifications have been aimed at deriving compounds with glucocorticoid
(and anti-inflammatory) actions but lacking in mineralocorticoid effects and
side effects. Substituents added to the cortisol molecule may alter
bioactivity and receptor binding affinity independently of other functional
groups present on the molecule.
O O
OH OH
HO HO OH
H H
H H H H
O O
Cortisol (15.1) Corticosteron (15.2)
7
1. Halogenation. 9 lfa-Fluorocortisone is only about 10 times more active
than its parent compound, but its mineralocorticoid activity is 300600 times
greater. This is undesirable since it leads to edema; thus, the compound
fludrocortisone (15.3) is used only topically, in ointments.
2. Additional double bonds. 1-compounds (where .1 indicates the position of a
double bond) were introduced, like prednisone (15.4), a .1-11-ketone, and
prednisolone, its 11-hydroxy analogue. Changing the geometry of the A ring
increased the potency without augmenting mineralocorticoid activity.
O
OH OH O
HO OH OH
O
H
H
F H
H H
O
Fluorocortison (15.3) O
Prednison (15.4)
8
The introduction of a methyl group in methylprednisolone (15.5) resulted
in a slight increase in activity; however, the greatest improvements in
activity came from the combination of a double bond, halogen, and
methyl substituents. Triamcinolone (15.6), in the form of its acetomide (an
acetone ketal), shows a 9-fluoro group in addition to .1 unsaturation,
and a 16-OH. It is used in treating psoriasis and other dermatological
problems.
O O
OH OH OH OH
HO HO
H H OH
H H F H
O O
O
OH OH
HO
H
H H
O
Dexamethason (15.7)
10
5.12.3 Glucocorticoids: Pharmacological Activity
11
Glucocorticoids: Inflammation versus Infection
12
Infections are usually accompanied by inflammation. The reddened
area around a skin abscess reflects the bodys inflammatory response
to the infection. If one puts topical steroids on such an infection, the
redness disappears, reflecting suppression of the inflammation and
giving the erroneous impression that the infection has been
successfully treated; in truth, the infection is now spreading much more
aggressively since the bodys inflammatory defense system has been
suppressed. Nevertheless, sometimes it is necessary to cautiously use
anti-inflammatory steroids in the presence of an infection. For
example, pneumonia may be associated with a dangerous
inflammation of the airways, causing decreased air entry into the
lungs. Under such circumstances, the combined use of an anti-
inflammatory steroid with the appropriate antibiotic is justified.
13
STEROID HORMONES:
ADRENOCORTICOIDSMINERALOCORTICOIDS
H H H H
O O
Aldosterone (15.8) 11-Deoxycorticosteron (15.9)
14
O
O
H
H O
H
O S
Spironolacton (15.10)
15
Structurally, aldosterone differs from glucocorticoids in having an 18-
aldehyde group and lacking the 17-OH. The aldehyde participates in
a tautomeric equilibrium, forming a cyclic hemiacetal ring.
Spironolactone, a synthetic compound and antiandrogen, has a
lactone ring attached to C-17 through one common carbon (a spiro
compound) and the 7-thiolester group. The structure of the
mineralocorticoid receptor has been deduced through cloning of its
cDNA. It shows considerable structural and functional similarity to the
glucocorticoid receptor.
16
The most important pharmacological action of glucorticoids
and their semisynthetic analogues is their
a. antiinflammatory
b. and antirheumatic activity, discovered in 1949 by
Hench and co-workers.
17
Relative glucocorticoid and mineralocorticoid activity of some corticoid
derivatives
Cortisol 1 1
Fluorocortison 10 300
Prednison 3 0,8
Methylprednisolone 5 0
Triamcinolone 6 0
Dexamethason 30 0
11-deoxycorticosterone 0 30
Aldosteron 0,2 600
18
Although the mode of action of glucocorticoids is unknown,
there are certain indications that:
19
These steroids are also effective:
20
LIPIDS AS DRUGS AND DRUG DESIGN TARGETS
21
As the research area expanded, the leukotrienes were
discovered next. The leukotrienes are potent lipid
mediators associated with asthma and allergic
reactions. In contrast to prostaglandins, leukotrienes
are made predominantly in inflammatory cells, like
leukocytes, macrophages, and mast cells.
Prostaglandins, thromboxane, and the leukotrienes are
lipids that are collectively called eicosanoids, since
they are all derived from the C20 fatty acid, arachidonic
acid [eicosa (Gr.) = twenty]. Over the past twenty years,
the eicosanoids have emerged as important molecules
around which to target drug design and development.
22
Prostaglandins, prostacyclin, and thromboxane are
considered local hormones or autocoid,
synthesized in many different organs and acting
locally. They are not stored like neurotransmitters
or conventional hormones, but are continuously
synthesized and released immediately into the
circulation, where they are usually deactivated after
only one passage through the lungs. The synthesis
depends on the availability of the starting material,
arachidonic acid, and is modulated by c AMP.
23
Prostaglandins A, PGB, PGC are inactive degradation products.
O O O OH O
PGB
O HO
PGA PGC PGD PGE
24
Figure 8.9 Prostaglandins and leukotrienes are potent eicosanoid lipid mediators, derived from
phospholipase-released arachidonic acids, that are involved in numerous homeostatic biological
functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase,
respectively, and their biosynthesis and pharmacological actions are inhibited by clinically relevant
nonsteroidal anti-inflammatory drugs.
25
Pharmacological effects of prostaglandins and thromboxane
26
The following effects of prostaglandins
27
3. The Oxytocic Activity of prostaglandin is used clinically.
Prostaglandin E2 can induce labor at term in pregnant women,
while PGF2 and its ester is probably due to a direct effect on
uterine muscle.
4. Other Effects of the prostaglandins include bronchodilatation
by the PGE series and constriction by PGF2, as well as anti-
ulcer and antisecretory effects of some synthetic analogues in
the stomach. It has been suggested that alcohol facilitates
arachidonic acid release and subsequent PGE2 synthesis, and
is indeed responsible for hangover headaches. The analgesic
tolfenamic acid (8.66) is alleged to have a preventive effect
hope springs eternal.
28
E. Antiinflammatory Agents and Minor Analgesic
29
8.5.1 Prostaglandins and Thromboxanes
8.5.1.1 Prostaglandins: Structure and Biosynthesis
The biosynthesis of prostaglandins and thromboxanes starts from
arachidonic acid. Arachidonic acid, obtained from its phospholipid
form by the action of phospholipase A, is cyclized to prostaglandin
endoperoxide (15.11) in the form of PGG (a side-chain peroxide), from
which PGH2 (a side-chain hydroxyl) is obtained.
O
CO 2H
OH
Prostaglandine Endoperoxide (15.11) 30
Interleukin-1, a cytokine produced by leukocytes and possessing
multiple immunological roles, mediates inflammation by increasing
phospholipase activity and thus prostaglandin synthesis. The first
reaction in prostaglandin biosynthesis is catalyzed by PG
cyclooxygenase in the presence of O2 and heme. The second
reaction requires tryptophan, probably as a source of electrons.
31
Structure of prostaglandin and thromboxanes
O
CO 2H
HO
PGE1 OH
O
7 4 2
1
10 CO 2H
20
HO 13
PGE2 OH
32
CH 2OCO(CH 2)nCH 3
O
C CH
O
CH 2OPOR
Phospholipid-esterified O
arachidonic acid
Phospholipase
CO2H
Phospholipid
Arachidonic acid
33
Phospholipase
CO2H
Phospholipid
Arachidonic acid
Corticosteroids
34
The non steroidal antiinflammatory agents block the cyclooxygenase
that converts arachidonic acid to PGG2 and PGH2. Since the cyclic
endoperoxidides are the prcursors of all prostaglandins, the synthesis
of the latter is interupted.
CO 2H
Arachidonic acid(AA)
AA cyclooxygenase
Non steroidal antiinflammatory agents
2 O2
O CO 2H
O[O]H
Prostaglandin endoperoxida
35
Leukotrienes,- which have been called slow-
reacting substance (SRS) -are compounds
intimately involved in anaphylactic reaction, allergic
reactions, and asthma. Like the prostaglandins,
thye are lipids, formed from arachidonic acid by
lipoxygenase and glutathione. Their structure and
biosynthesis were also elucidated by the
Samuelsson group (Samuelsson, 1980), and are
shown in Fiq.
36
CO 2H
Arachidonic acid(AA)
Lipoxygenase
H OOH
CO 2H
5-HPETE
O
CO 2H
C5H11
Leukotriene A (LTA)
37
Anti-Prostaglandins as Anti-Inflammatory
Agents and Minor Analgesics
38
1) NSAIDs: Non-selective cyclo-oxygenase inhibitors
39
The nonsteroidal anti-inflammatory agents block the
cyclooxygenase enzyme that catalyzes the
conversion of arachidonic acid to the prostaglandins
PGG2 and PGH2. Since these two cyclic
endoperoxides are the precursors of all other
prostaglandins, the implications of cyclooxygenase
inhibition are significant. Prostaglandin E1 is known
to be a potent pyrogen (fever-causing agent), and
PGE2 causes pain, edema, erythema (reddening of
the skin), and fever. The prostaglandin
endoperoxides (PGG2 and PGH2) can also produce
pain, and inhibition of their synthesis can thus
account for the action of the nonsteroidal anti-
inflammatory agents.
40
Most of the nonsteroidal anti-inflammatory drugs (NSAIDs) are
carboxylic acids. Aspirin (8.69) (acetylsalicylic acid, ASA) has
been used since the turn of the last century to reduce pain and
fever, but the parent compound, salicylic acid, has been known
and used since antiquity, owing to its common occurrence as a
glycoside in willow bark. Acetylation merely decreases its
irritating effect. Among the numerous other salicylates known and
used, flufenisal (8.70) has a longer duration of activity and fewer
side effects than aspirin.
41
Mefenamic acid (8.71) and flufenamic acid (8.72) are derivatives of
anthranilic acid, while ibuprofen (8.73) and naproxen (8.74) are
derivatives of phenylacetic and naphthylacetic acids, respectively.
42
Among indole derivatives, indomethacin (8.75) is very widely used despite side
effects. Its indene analog sulindac (8.76) is a pro-drug, the active form being
its SH derivative. Piroxicam (8.77) is a long-lasting anti-rheumatoid agent
but can have serious gastrointestinal side effects. The once widely used
phenylbutazone (8.78) derivatives have too many side effects and have fallen
into disrepute.
43
Among the nonselective cyclooxygenase (COX) inhibitors,
there is no clear-cut statistical evidence for the superiority of
one or another of these useful drugs. Individual patients may
do better with some than with others, and there are
differences in side effects, primarily gastric bleeding and
renal toxicity, which can be especially serious with the
prolonged administration of high doses necessary in chronic
diseases such as rheumatoid arthritis. Some of these
compounds are powerful enough to be effective against the
major pain caused by malignancies.
44
Most of the nonsteroidal antiinflammatory drugs
are carbocylic acids, Aspirin (acetylsalicylic acid,
ASA), has been used since the turn of the century to
reduce pain and fever, but the parent compound,
salicylic acid, has been known and used since
antiquity, owing to its common occurrence as a
glycoside in willo bark. Acetylation merely
decreases its irritating effect. Among the numerous
other salicylates known and used, flufenisal has a
longaer duration of activity and fewer side effects
than aspirin.
45
In theory the selective COX-2 inhibitors may offer some advantages.
There are at least two forms of the COX enzyme: COX-1 and COX-2.
COX-1 is located in most tissues, including stomach and kidneys.
COX-2, on the other hand, is undetectable in most tissues under
physiological conditions. COX-2 is induced at sites of inflammation,
secondary to the effects of cytokines. Accordingly, specific COX-2
inhibitors, such as celecoxib (8.79) and rofecoxib (8.80), are less likely
to cause stomach ulceration and gastrointestinal bleeding.
Nevertheless, they still have the capacity to cause fluid retention and
renal damage. More significantly, in 2004 it was recognized that COX-
2 inhibitors may pose an increased cardiovascular risk. For example,
rofecoxib was suddenly withdrawn from the market when it was noted
that there was an increased relative risk for confirmed cardiovascular
events, including heart attack and stroke, beginning after 18 months
of treatment, compared to placebo.
46
47
Anti-Leukotrienes as Anti-Inflammatory
Agents for Asthma
Like the other eicosanoids, the leukotrienes are also involved in inflammatory
diseases. Accordingly, leukotriene pathway inhibitors are emerging as
important agents. Two fundamental approaches to the design of leukotriene
pathway inhibitors have been pursued:
48
49
COOH COOH
F
OC CH 3 OC CH3
Aspirin Flufenisal
O O
Mefenemic acid and flufenamic acid are derivatives of anthranilic acid,
while ibuprofen and naproxen are derivatives of phenyl acetic acid and
naphthylacetic acid, respectively.
COOH
COOH
NH
NH
CH 3
CF 3
CH 3 Flumefenemic Acid
Mefenemic Acid
50
CH 3
CH 3
CH COOH
CH COOH
H3CO
Naproxen
H H2
H2C C CH 3 C COOH
CH 3
Ibuprofen H3CO N CH 3
C O
Cl
Indomethazcin
51