Al-Esraa University College

Pharmaceutical Chemistry II
Dr. Hany Hafez

‫قسم الصيدلة – كلية اإلسراء‬

2 ‫ الكيمياء الصيدلية‬- ‫المرحلة الرابعة‬
1 ‫المحاضرة‬
25 – 09- 2023
 Endocrine System

The endocrine system refers to the collection of ductless

glands of human body that secrete hormones directly into
the spaces surrounding their cells (interstitial fluid) and
blood to be carried towards distant target organs e.g.
pituitary gland

The endocrine system's effects are slow to initiate, and

prolonged in their response, lasting from a few hours up
to weeks.
 Hormones
 They are chemical messengers that bind to receptors on
target cells, which leads to some change in that cells
physiologic state. They affect the cell that made them or a
cell distant to their origin.
 These messengers control the most major body functions by
interacting with target cells which bear specific receptors for
that particular hormone.
 Hormones
 Hormones play a role in the regulation of metabolism,
reproduction, development and growth.
 Hormones
• Hormones bind to their specific receptors according to lock
& key model
 Classification of hormones
According to secreting organ:
1. Hypothalamus
2. Pituitary gland
• Anterior pituitary lobe
• Posterior pituitary lobe
3. Thyroid
4. Digestive system: Pancreas
5. Adrenal glands
6. Reproductive: Testes & Ovaries
 Classification of hormones

According to chemical structure:

1. Steroid hormones are fat-soluble molecules made from cholesterol e.g.
estrogens and androgens.
2. Aromatic amino acid derivatives, such as epinephrine, are water-
soluble molecules derived from amino acids
3. Peptides or Protein hormones: These hormones are formed of:
Large polypeptides: e.g. Insulin.
Small polypeptides: e.g. ADH
4. Fatty acid derivatives: Prostaglandin (Prostaglandins).
Classification of hormones
 Hypothalamic hormones
I. Affect the anterior pituitary gland:
1. Growth hormone-releasing hormone (GHRH) or growth hormone-inhibiting hormone (GHIH)
(also known as somatostatin):
2. Thyrotropin releasing hormone (TRH):
3. Corticotropin-releasing hormone (CRH):
4. Gonadotropin-releasing hormone (GnRH):
5. Prolactin-inhibiting hormone (PIH) (also known as Dopamine):
(N.B. Prolactin-releasing hormone (PRH) is a hypothetical hormone)

II. Affect the posterior pituitary gland:

1. Anti-diuretic hormone (ADH):

2. Oxytocin:
All Hypothalamic hormones (except PIH) are polypeptide.
 Steroids
Steroid hormones are steroids that act as
hormones.
• They are all derived from the parent compound
cholesterol
• They are not stored in tissues, but are
synthesized and immediately release
• They are synthesized & secreted from Adrenal
Gland, Ovary & Testes.
• They are not water soluble so have to be carried
in the blood complex to specific binding globulins
(plasma protein)
 Classes of Steroid Hormones

Steroid hormones can be grouped into 2 classes, corticosteroids

and sex steroids
1. Glucocorticoids; cortisol is the major representative in most
mammals
2. Mineralocorticoids; aldosterone being most prominent
3. Androgens such as testosterone
4. Estrogens, including estradiol and estrone
5. Progestins such as progesterone
Steroid
Hormones

Glucocorticoids Mineralocorticoid Androgen Estrogens Progestogens

Cortisol Aldosterone Testosterone Estradiol Progesterone
 Basic structure of steroids
• The basis of a steroid molecule is a four-ring structure: three six-
membered Cyclohexane ring (A, B & C) and one five-membered
Cyclopentane ring (D) in a fused ring system.

• The prototype steroid skeleton is named Cholestane.

IUPAC recommended ring lettering (left) and atom numbering (right)

of the steroid skeleton. The four rings A-D form a sterane core.
 Steroid Stereochemistry and Shape
Steroid Conformation
It is based on cyclohexane chair conformation
 Steroid Conformation
The 5α-isomer (Trans A/B) is 0.18 kcal/mol lower in energy (more stable) than the 5β-
isomer
 Steroids Nomenclature
Most steroids can be classified as belonging to one of
four main ring systems. These are:
Cholestanes
The distinguishing characteristics of Cholestanes are:
 The basic skeleton is consisted of 27 carbon atom
 Two methyl groups, one at C-13 and the other at C-10
 An 8-carbon side-chain attached at C-17
Pregnanes
The distinguishing characteristics of Pregnanes are:
 The basic skeleton is consisted of 21 carbon atom
 Two methyl groups, one at C-13 and the other at C-10
 A two carbon side chain at the 17-position
 Steroids Nomenclature
Androstanes
The distinguishing characteristics of androstanes are:
• The basic skeleton is consisted of 19 carbon atom
• Two methyl groups, one at C-13 and the other at C-10
• No side chain at the 17-position
Estranes
The distinguishing characteristics of Estranes are:
• The basic skeleton is consisted of 18 carbon atom
• Only one methyl substituent at C-13
• No side chain at the 17-position
 Glucocorticoids
Major Natural Glucocorticoids
 Glucocorticoids (GCs) are a class of corticosteroids, which in
turn are a class of steroid hormones.
 Glucocorticoids are corticosteroids that bind to the
glucocorticoid receptor (GR).
 The name glucocorticoid (glucose + cortex + steroid) derives
from its role in the regulation of the metabolism of glucose, its
synthesis in the adrenal cortex, and its steroidal structure (see
structure to the right).
 Glucocorticoids
Major Natural Glucocorticoids
 The principal Glucocorticoids, Cortisol, is
secreted by the adrenal cortex in response to
internal or external stress Cortisol (or
hydrocortisone) is the most important human
glucocorticoid.

 It is essential for life, and it regulates or

supports a variety of important cardiovascular,
metabolic (carbohydrate& bone), immunologic
(inflammatory responses) and homeostatic
functions.
 Natural Glucocorticoids

Cortisol Cortisone
(Hydrocortisone)

Cortisol: (11β)-11, 17, 21-trihydroxypregn-4-ene-3, 20-dione

Cortisone: 17, 21-dihydroxy-pregn-4-ene-3,11,20-trione
Biosynthesis of cortisol
 Synthetic Glucocorticoids
 They have the major function as Natural Glucocorticoids.
 These are used either as replacement therapy in
glucocorticoid deficiency or to suppress the immune system
and inflammation.
 They are usually more potent (5-100 times) & have less or no
mineralocorticoids activity
 They are chemically more stable and administered as tablets,
injections, creams & eye drops ….
 They are effective as an immunosuppressant drug.
 Synthetic Glucocorticoids
1. Prednisone: 17, 21-dihydroxypregna-1,4-diene-3,11,20-
trione

• Prednisone is a synthetic corticosteroid drug

• It is a prodrug that is converted in the liver to the active form,

Prednisolone
 Synthetic Glucocorticoids
2. Prednisolone: 11β,17,21-trihydroxypregna-1,4-diene-3,20-
dione

 Prednisolone is a synthetic glucocorticoid, a derivative of

cortisol.
 Fluorinated Glucocorticoids
3. Betamethasone: 9-fluoro-11β,17,21-trihydroxy-16β-
methylpregna-1,4-diene-3,20-dione
• Betamethasone doesn’t cause water retention unlike
other corticoids.

• It is used for rheumatoid arthritis, dermatitis, psoriasis,

allergic conditions such as asthma and cancers such as
leukemia.
 Synthetic Glucocorticoids
4. Dexamethasone
 It is the same as Betamethasone except it may cause
sodium water retention
 It is more potent than natural corticosteroids (27 times)
and prednisone (7 times).
 Glucocorticoids uses
1. Inflammatory disorders:
 Rheumatoid arthritis, gout
 Inflammatory bowel disease (ulcerative colitis)
2. Eye Inflammation : conjunctivitis
3. Immunological disorders:
 Immune suppression to prevent transplant rejection
4. Respiratory condition: asthma
5. Skin disorders: eczema - psoriasis
 Structure activity relationships of glucocorticoids
1. The all-trans (A/B, B/C and C/D) backbone that is necessary
for activity is very evident.

2. A carbonyl group at C3, a double bond between carbons 4 and

5, an oxygen (C=O or β-OH) at carbon 11, and a β-ketol side
chain at position 17 are necessary for superior glucocorticoid
activity more than mineralocorticoid activity.
Structure activity relationships of glucocorticoids
3. The introduction of C1=C2 function increases potency &
glucocorticoid receptor (GR) affinity and alters pharmacokinetics
(primarily metabolism, Ring A is much more slowly metabolized) due
to the change in geometry (conformation ) of ring A from a chair, as
in 5α-pregnan-3-one, to a half-chair (pregn-4-en-3-one) and to a
flattened boat (pregna-1,4-dien-3-one)
Structure activity relationships of glucocorticoids
4. The 11β-OH group of hydrocortisone is involved in the drug–
receptor interaction. Cortisone, which contains an 11-keto
function, is reduced in vivo to hydrocortisone.
 (11B-OH has superiority over 11-keto compound)
Structure activity relationships of glucocorticoids
5. Halogens may introduced into the 9α-position, the 9α-F group
increases glucocorticoid activity and nearly prevents metabolic
oxidation of the 11β-OH group to a ketone.
 9α-F group may increase activity by an inductive effect, which
increases the acidic dissociation constant of the 11β-OH group
and, thereby, increases the ability of the drug to hydrogen
bonding to GRs.
The 9α-fluoro analogue (fludrocortisone) is
approximately 11 times as potent as cortisone
acetate & mineralocorticoid activity is increased
300 to 800 times.
Structure activity relationships of glucocorticoids
6- Glucocorticoid activity is inversely proportional to the size of
the halogen at carbon 9.
 Beclomethasone, a 9α-chloro analogue of betamethasone, is a
potent glucocorticoid with approximately half the potency of
its fluoro analogue but it has higher stability, lipophilicity &
duration of action (topical use)

7. Inserting a 16α-hydroxy group into 9α-

fluoroprednisolone resulted in the same
glucocorticoid activity but decreasing
mineralocorticoid activity.
Structure activity relationships of glucocorticoids
8. A 16α-methyl group does decrease the reactivity of the 20-
keto group to carbonyl reagents and increases the stability of
the drug in human plasma.
 Unlike 16α-hydroxylation, a methyl group increases the anti-
inflammatory activity by increasing lipophilicity and, receptor
affinity.
 Like the 16α-hydroxyl group, the methyl group appears to
reduce markedly the salt-retaining properties of the
corticosteroids
Structure activity relationships of glucocorticoids
9. Esterification at C-17 & C-21 Hydroxyl group produces
prodrugs.
 Mineralocorticoids

 Mineralo-Corticoids are a class of steroid hormones

similar to aldosterone in their effects on salt & water
balances.
 The name mineralocorticoids derives because these
hormones are involved in the retention of sodium (Na), a
mineral
 Aldosterone is primary endogenous mineralocorticoids
 Aldosterone
Detailed action mechanisms
• It acts on the mineralocorticoid receptors (MR) in the distal
tubule & it upregulates and activates the Na+/K+ pumps,
which reabsorbs three sodium ions into the blood and two
potassium ions into the urine.

• This is in an increase of blood pressure & blood volume

 It is 11β,21-Dihydroxy-3,20-dioxopregn-4-en-18-al
Biosynthesis of Aldosterone
 Structure activity relationships of
mineralocorticoids
1. Highly active natural mineralocorticoids have no OH function in
positions 17.
 In fact, OH groups in any position reduce the sodium-retaining activity
of the adrenocorticoid.
2. 9α-F, 9α-Cl , and 9α-Br substitution causes increased retention of
urinary sodium with an order of activity in which F > Cl > Br
3. Insertion of a 16α-OH group into the molecule affects the sodium
retention activity so markedly that it not only negates the effect of the
9α-F atom but also causes sodium excretion
 Structure activity relationships of
mineralocorticoids
4. A double bond between positions 1 and 2 (C1-corticoids) also reduces
the sodium retention activity of the parent drug.
 It contributes to the parent drug only approximately one-fifth the
sodium-excreting activity of a 16α-OH group
5. A 17α-OH group reduces sodium retention as the unsaturation between
positions 1 and 2.
6. Other substituents reported to inhibit sodium retention include 16α-
CH3, 16β-CH3 and 16α-CH3O functions.
 Mineralocorticoids related products

 There is no prescription products containing aldosterone as

the active ingredient
 It is available mainly in analytical kits to estimate the
levels of this hormone in patients
 The technique used is known as ELISA (enzyme linked
immune sorbent assay) which is a wet lab type analytical
biochemistry
 Drugs used as mineralocorticoids
Fludrocortisone
• Fludrocortisone is used only for the treatment of Addison disease
and for inhibition of endogenous adrenocortical secretions.
• it has up to about 800 times the MC activity of hydrocortisone and
about 11 times the GC activity
• Although its great salt-retaining activity limits its use to Addison
disease, it has sufficient GC activity that in some cases of the
disease, additional GCs need not be prescribed.
 Mineralocorticoids antagonists
Spironolactone
• It is a synthetic steroid that blocks mineralocorticoid
receptors. It also blocks androgen, and blocks progesterone
receptors. It belongs to a class of medications known as
potassium-sparing diuretics.
• It is used as a diuretic and antihypertensive drug under the
name of Aldactone
 Eplerenone
It is similar to the diuretic spironolactone, though it is much
more selective for the mineralocorticoid receptor in
comparison (i.e., does not possess any antiandrogen,
progestogen, glucocorticoid, or estrogenic effects)
 Sex Hormones
1. Progestins
• The natural progestational hormone is progesterone, which is secreted
by the corpus luteum in the second part of the menstrual cycle.

• Progesterone: Pregn-4-ene-3,20-dione
 Progestins
Physiological activity of natural progesterone
Maintenance of pregnancy
Inhibition of spontaneous uterine contractions
Inhibition of follicular maturation & ovulation
Uses
Prevent habitual abortion
Oral contraceptives
Biosynthesis of progesterone
Progesterone derivative & synthetic progestins
 SAR:
– Steroidal nucleus essential for activity.
– Have some androgenic activity.
– Removal of the 19 CH3 increase activity.
– Unsaturation of ring B or C increase the activity.
– Removal of the keto function remove androgenic activity.
 Progestin Antagonists
• Mifepristone:
– Compete with the progestin receptors.
• Uses:
– Contraceptive - Abortifacient.
 Sex Hormones
Androgens
 Androgens are any natural or synthetic compound, usually steroid hormones
that stimulate or control the development and maintenance of male
characteristics in human by binding to androgen receptors.
 This includes the activity of the primary male sex organs and development of
male secondary sex characteristics.
 Androgens are also the original anabolic steroids and the precursor of all
estrogens.
 The primary and most well-known androgen is Testosterone.
 Dihydrotestosterone (DHT) and Androstenedione are less known generally,
but are of equal importance in male development.
 Androgen biological effects
Androgenic effects include
1. Maturation of the sex organs
2. At puberty, a deepening of the voice, growth of the beard and axillary hair.
Anabolic effects include
1. Growth of muscle mass and strength,
2. Increase bone density and strength.
 Androgen structure

Testosterone Dihydrotestosterone (5α-DHT)

 Steroid skeleton of 19 carbon atoms
 Oxygen substituents at C3 & C17

Testosterone: 17B-Hydroxyandrost-4-en-3-one
Dihydrotestosterone (5α-DHT): 17B-Hydroxyandrostan-3-one
4-Androstenedione: androst-4-ene-3,17-dione
 Synthetic androgens
Nandrolone Fluoxymesterone
 Pharmaceutical testosterone esters
 They are administered by oral or injectable routes
 The longer hydrocarbon chain the more fat soluble and longer duration of action
 Undecanoate < Decanoate< Enanthate< Isocarpoate
 SAR of Androgens
1.For a substance to have activity ,it must contain the andostane skeleton.

3.The basic nucleus having 5-α-androstane which having androgenic activity

,whereas 5-β-androstane having no activity. Why?

4.There should not be ring A constriction or extension because it leads to

destroys the androgenic and anabolic activities.
 SAR of Androgens
5. Introduction of 3-hydroxy group and 3-keto group enhance the activity.

6. α-Hydroxy group at C-17 position has no androgenic or anabolic activity

but 17β (OH) is important for activity due to attachment to the receptor site.

7. 17α-alkyl groups are important for preventing metabolic changes at

this position so that such 17α-substituents render the compounds
orally active because the alkylated derivatives are slowly catabolized
by the liver.
 SAR of Androgens
8. Halogen substitution produces compounds with decreased activity except
when placed at C-4 or C-9 position.
 For example , 9-fluoro derivatives produces an anabolic effect 20 times
that of 17 alpha-methyl testosterone
9.Introduction of double bond at C-1 position increases
the anabolic activity for example – methandrostenolone
is more active than methyltestosterone
 SAR of Androgens
9. Esterification of the 17-β hydroxyl group with carboxylic acids
decreases the polarity of the molecule, makes it more soluble in the
lipid vehicles used for injection, and, hence, slows the release of the
injected steroid into the circulation. The longer the carbon chain in
the ester, the more lipid-soluble it is, and the steroid becomes
more prolonged in action
 Metabolism of Androgens
Testosterone undergoes metabolism that may lead to either
1. active steroids e.g.,
a) 5α-dihydrotestosterone (or 5α-DHT) by the action of 5-reductase in prostate,
skin & liver.
b) estradiol by the action of aromatase in adipose tissues.
2. inactive steroids e.g., 6α-hydroxytestosterone

 Both 5α-reduction and

aromatization are irreversible
processes.
 Estrogens
• Estrogen is the primary female sex hormone and is responsible for
development and regulation of the female reproductive system and
secondary sex characteristics.

• Estrogen may also refer to any substance, natural or synthetic, that

mimics the effects of the natural hormone.

• Natural estrogens are steroid hormones while synthetic estrogen are

non-steroid hormones

• They bind to and activate estrogen receptors (ERs)

 Estrogens
 The three major naturally occurring forms of estrogen in women are
Estrone (E1), Estradiol (E2), And Estriol (E3). Estetrol (E4) is produced
only during pregnancy.

 Synthetic estrogens are used as oral contraceptives, in estrogen replacement

therapy for postmenopausal women, Cosmetic dermatology, and in hormone
replacement therapy for trans women.
 Female sex steroid hormones

Estrone (E1) Estradiol (E2) Estriol (E3)

The most important estrogen feature is aromatic ring A
 Estrone: 3-Hydroxyestra-1,3,5(10)-triene-17-one
 Estradiol: 3,17β- Dihydroxyestra-1,3,5(10)-triene
 Estriol: 3,16, 17β-Trihydroxyestra-1,3,5(10)-triene
 Physiological activity of natural estrogens

 Reproduction & development of female sex organs

 They promote the development of female secondary sexual
characteristics, such as breasts,
 Role in ovulation & pregnancy
 Role in mineral (Ca), carbohydrate, protein& lipid metabolism
 Increase bone formation
 Estrogen Therapeutic Uses
 Oral contraceptives combination with progestin to reduce circulating
levels of FSH and LH, by negative feed-back mechanism so that it
blocks ovulation
 Hormone replacement therapy: to prevent osteoporosis as well as
treat the symptoms of menopause such as hot flushes
 Breast cancer: Hormone-receptor-positive breast cancers are treated
with drugs which suppress production or interfere with the action of
estrogen in the body. This technique is known variously as hormonal
therapy, hormone therapy, or anti-estrogen therapy
 Cosmetic dermatology
Biosynthesis of estradiol
 Aromatase: Estrogen Synthetase
 Aromatase, also called estrogen synthetase or estrogen synthase.
 It is an enzyme responsible for a key step in the biosynthesis of
estrogens. It is a member of the cytochrome P450 superfamily.
 Aromatase is responsible for the aromatization of androgens into
estrogens.
 It is an important factor in sexual development.
 Synthetic estrogen (orally active)
Ethinyl estradiol
 Ethinyl estradiol (EE2) is a derivative of 17β-estradiol (E2), the major
endogenous (natural) estrogen in humans.

 EE2 has ethinyl group in the 17 position.

 EE2 is an orally bioactive estrogen used in many formulations of

combined oral contraceptive pills with progesterone once daily.
 Mestranol
 Mestranol is the 3-methyl ether of ethinyl estradiol
 It is a biologically inactive prodrug of ethinyl estradiol to which it is
demethylated in the liver .
 It was employed as the estrogen component in many of the first oral
contraceptives
 Mestranol has been used as a component of hormone replacement
therapy.
 SAR of estrogen
1. Steroid nucleus is not necessary for estrogenic activity
 Many constituents of plants like genstein ,coumestrol
don’t contain steroid nucleus but possess estrogenic
activity

2. Estradiol is not effective orally due to rapid metabolism in liver but placement of
ethinyl group at C-17 position increase the resistance to metabolic inactivation and
make the compound orally effective .
 SAR of estrogen

4. Similarly methylation of 3-OH group e.g. mestranol make the compound

orally effective
5. Ester derivatives (acetates and benzoates) of the naturally occuring and
synthetic estrogens have prolonged action.
6. Insertion of OH group at C-6,C-7 and C-11 position reduces estrogenic
activity.
 Non-steroidal estrogen
Diethylstilbestrol (DES)
• Diethylstilbestrol (DES) is a synthetic, non-
steroidal estrogen of the stilbestrol group
• From about 1940 to 1971, DES was given to
pregnant women in the mistaken belief it would
reduce the risk of pregnancy complications and
losses.
• In 1971, DES was shown to cause clear cell
carcinoma, a rare vaginal tumor in girls and women
who had been exposed to this drug in uterus
• It is still used to treat breast and prostate cancers.
 Schuler’s hypothesis for synthetic estrogen

 This hypothesis attempts to explain the estrogenic effect of

synthetic non-steroidal estrogens

 It is based on geometric, dimensional (linear & 3D), steric and

stereo chemical similarity parameters

 Sechuler proposed a hypothesis that has now been supported

by numerous molecules.

 He proposed that the critical thing is the distance the between

the two oxygens. It should be 12.1 Å.
 Sechuler’s hypothesis for synthetic estrogen

 This is an overview of how

the two molecules look top
view and side view.
 When a water molecule is
added to estradiol the
overlay shows superposition
of the two oxygens.
 Schuler's hypothesis is now
considered to be most
probably true.
 Selective Estrogen Receptor Modulator
Selective estrogen receptor modulators (SERMs) are a class of
drugs that act on the estrogen receptor (ER).
 A characteristic that distinguishes these substances from pure
ER agonists and antagonists (that is, full agonists and silent
antagonists) is that their action is different in various tissues,
thereby granting the possibility to selectively inhibit or
stimulate estrogen-like action in various tissues.
SERMs are competitive partial agonists of the ER.
 Selective Estrogen Receptor Modulator
 Different tissues have different degrees of sensitivity to and activity of
endogenous estrogens, so SERMs produce estrogenic or antiestrogenic
effects depending on the specific tissue in question as well as the
percentage of intrinsic activity (IA) of the SERM.

 SERMs like clomifene and tamoxifen are more in the middle in their IA
and their balance of estrogenic and antiestrogenic actions in comparison.
 Selective Estrogen Receptor Modulator
 Raloxifene is a SERM that is more antiestrogenic than tamoxifen; both
are estrogenic in bone, but raloxifene is antiestrogenic in the uterus
while tamoxifen is estrogenic in this location.
 It is used as a hormonal treatment to treat and prevent breast cancer.
 Tamoxifen is a first-line hormonal treatment of ER-positive metastatic
breast cancer.
 Benefits of SERMs
SERMs are used for various estrogen-related diseases including:
1. Treatment of ovulatory dysfunction in the management of
infertility
2. Treatment and prevention of postmenopausal osteoporosis
3. Reduction in risk of breast cancer
4. SERM is also used in combination with conjugated estrogens
indicated for the treatment of estrogen deficiency symptoms,
and vasomotor symptoms associated with menopause.
 Pattern of action of SERM
SERMs are used dependent on their pattern of action in various
tissues:

Name Uses Effects/location

Ovulation induction in
Clomifene Antagonist at hypothalamus
anovulation

Agonist at bone; antagonist

Ormeloxifene Contraception
at breast and uterus

Agonist at bone; antagonist

Raloxifene Osteoporosis, breast cancer
at breast and uterus

Agonist at bone and uterus,

Tamoxifen Breast cancer
antagonist at breast
 Example of SERMs

Clomiphene Tamoxifen
 Thyroid Hormone
 Endocrine System
 Thyroid Gland
 Regulation of Secretion of Thyroid Gland
 Thyrotropin (TRH) stimulate the anterior pituitary to secrete
thyroid stimulating hormones (TSH)
 TSH stimulate thyroid gland to secrete thyroid hormones T3
& T4
 When blood concentration of T3 & T4 is increased above a
certain threshold, TRH secretion in the hypothalamus is
inhibited
 As thyroid hormone levels decrease below the threshold,
Negative Feedback is relieved, TRH secretion starts again,
leading to TSH secretion then thyroid hormones release again
 Thyroid Hormone
 The thyroid gland secrete 3 hormones
1. Polypeptide hormones: Calcitonin
2. Iodinated hormones: they are tyrosine-based hormones
a) Triiodothyronine (T3)
b) Tetraiodothyronine (T4, Thyroxine)
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is produced in
humans by the thyroid
MOA: It counteract parathyroid action, It lowers calcium conc. in blood by
1. Inhibition of osteoclast activity thereby reducing the rate of bone resorption
2. Inhibition of Ca absorption (intestine)& reabsorption (kidney)
Action & uses: Hypocalcemic hormones so, it used to treat hypercalcemia e.g.
postmenopausal osteoporosis
 Iodinated thyroid hormones
1. Triiodothyronine (T3)
2. Tetraiodothyronine (T4, Thyroxine)
 The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer
half-life than T3.
 In humans, the ratio of T4 to T3 released into the blood is roughly 20 to 1.
 T4 is converted to the active T3 (three to four times more potent than T4) within cells
by deiodinases (5'-iodinase).
 Both are derived from modification of tyrosine & are partially composed of iodine.
 Biosynthesis of T3 & T4
1. Uptake of iodide
2. Oxidation of iodide (peroxidase)
3. Iodide Organification: Iodination & coupling of tyrosine in thyroglobulin
(MIT & DIT) by (peroxidase)
4. Formation of thyroxine (T4) and triiodothyronine (T3) from iodotyrosine
5. Secretion of thyroid hormones (proteolytic enzymes)
6. Peripheral T4 to T3 by deiodinase
 Biosynthesis of T3 & T4
1. Uptake of iodide
2. Oxidation of iodide (peroxidase)
3. Iodide Organification: Iodination & coupling of tyrosine in thyroglobulin
(MIT & DIT) by (peroxidase)
1. Formation of thyroxine (T4) and triiodothyronine (T3) from iodotyrosine
2. Secretion of thyroid hormones (proteolytic enzymes)
3. Peripheral T4 to T3 by deiodinase
 FUNCTION OF THYROID HORMONES
 It is likely that all cells in the body are targets for thyroid hormones.
 The thyroid hormones are responsible for:
(not strictly necessary for life, but for "big time" processes)
1. Development of brain
2. Optimal growth e.g. in childhood.
3. Metabolism e.g. fat & carbohydrate
4. Body Function: oxygen requirement, Breathing, HR, Body weight, Muscle strength,
Menstrual cycles, Body temperature, Cholesterol levels, Much more!

Symptoms of Hyperthyroidism: Symptoms of Hypothyroidism:

1. Anxiety 1. Trouble sleeping
2. Irritability or moodiness 2. Tiredness and fatigue
3. Nervousness, hyperactivity 3. Depression- Difficulty concentrating
4. Sweating or sensitivity to high temperatures 4. Sensitivity to cold temperature
5. Hair loss 5. Dry skin and hair
6. Missed or light menstrual periods 6. Frequent, heavy periods
7. Hand trembling (shaking) 7. Joint and muscle pain
 Synthetic Thyroid Hormones

Levothyroxine Liothyronine
O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-2- O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-2-tyrosine
tyrosine monosodium salt monosodium salt

Uses : treatment of Hypothyroidism

N.B. iodine and iodides may be used for treatment of Hypothyroidism
Reasons for its use:
Stability - content uniformity - low cost - long half-life (7days) - once a
day dosing - lack of allergenic foreign protein - easy laboratory
measurements of serum levels
 SAR of T3 & T4

1. Aliphatic Side Chain: COOH, 2 C side chain are essential

2. Alanine Bearing Ring: ring & I are essential
3. Bridging Atom: essential (O,S,CH2)
4. Phenolic Ring: F < Cl < Br < I in activity (bulk & lipophilicity)
5. Phenolic Hydroxyl Group: essential for H- bonding
CH3 loss ,NH2 decrease, H pertain activity
Metabolism
 Antithyroid Drugs
1. Thioamides
a) Thiouracil: Methyl Thiouracil, Propyl Thiouracil & Benzyl Thiouracil
b) Thioimidazole (Sulfer containing imidazole ): Methimazole & Carbimazole
Thioamides
 Thioamides are simple molecules containing thiourea moiety within a heterocyclic
structure
 The basic thiocarbamide group is essential for antithyroid activity
 Thiourea and related compounds show an antithyroid activity, but they are too toxic for
clinical use.
 Thiouracil (Sulfated Uracil)
MOA
1. They inhibit thyroid peroxidase so that they prevent
 Iodine Organification i.e. the iodination of the precursors of T4 and T3
 Coupling
2. They inhibit deiodinase so that they prevent peripheral deiodination of T4 to T3
N.B. There is a delay in appearance of its effects because they affected synthesis rather
than release or activity of T4 so that it takes 4 week until depletion of T4 stores
Uses:
1. Hyperthyroidism (thiouracil can be only used in pregnancy temporarily)
a. Grave’s Disease
b. Goiter
c. Thyrotoxicosis
 Thioimidazoles
 Carbimazole is a pro-drug as after absorption it is converted to the active form,
Methimazole
 It is 10 times more potent than propylthiouracil
MOA: the same as general thioamides except No.2

SAR:
 Unsubstituted cyclic N and enolic / thioenolic function is a must
 Alkyl substituent at C5 and C 6 enhance activity
 The ester function of carbimazole (prodrug) improves the taste and acts as a slow
source for methimazole release
 Anion Inhibitors
They inhibit iodine uptake
Examples: Perchlorate (ClO4-) - Thiocyanate (SCN-)

Iodine and Iodides

MOA:
 Inhibit Iodine Organification (peroxidase)
 Inhibition of T3 & T4 release and synthesis
 Decrease of size & vascularity of the thyroid gland
Pharmacological effects
(1) Small doses: simple goiter
(2) Larger doses: inhibiting the release of thyroid hormones (proteolysis ) and
synthesis
 Radioactive Iodine
 131I is the only isotope used for treatment of thyrotoxicosis
 Therapeutic effect depends on emission of  rays

Adrenoceptor-Blocking Agents
Pharmacological effects
(1) Heart: 1 block
(2) CNS: relieving anxiety
(3) Presynaptic 2 receptor: NE release 
2. Clinical uses
Adjuvant therapeutic drug in thyrotoxicosis
Examples : Metoprolol – Propranolol - Atenolol