امتحان كيمياء عضويه كامل

10/11/2022
ADRENERGICS
DRUGS
© Oxford University Press, 2013
1. Nerve transmission
Peripheral nervous system
Skeletal
muscle
CNS (NR)
(Somatic) Ach
CNS
(Autonomic) Synapse
Sympathetic Ach NA AR
NR
Adrenaline
Ach Adrenal
Parasympathetic medulla Synapse AUTONOMIC
(NR)
Ach Ach MR
NR
Ach = Acetylcholine Smooth muscle

NA = Noradrenaline Cardiac muscle
AR = Adrenergic receptor MR & AR
NR = Nicotinic receptor
MR = Muscarinic receptor © Oxford University Press, 2013
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2. Adrenergic receptors (adrenoceptors)
Notes
•Two types of adrenoceptor (a and b)
•Subtypes (a1 and a2; b1, b2 and b3)
•Subtypes of subtypes (a1A a1B a1D a2A a2B a2C)
•G-protein coupled receptors

Distribution and effects
Organ or tissue Predominant adrenoceptors Effect of activation Physiological effect
Heart muscle 1 Muscle contraction Increased heart rate and
force
Bronchial smooth muscle 1 Smooth muscle contraction Closes airways
2 Smooth muscle relaxation Dilates and open airways
Arteriole smooth muscle (not Smooth muscle contraction Constricts arterioles and
supplying muscles) increases blood pressure
(hypertension)
Arteriole smooth muscle 2 Smooth muscle relaxation Dilates arterioles and

(supplying muscles) increases blood supply to
muscles
Veins 1 Smooth muscle contraction Constricts veins and
increases blood pressure
(hypertension)
2 Smooth muscle relaxation Dilates veins and decreases
blood pressure (hypotension)
GI tract smooth muscle Relaxation Shuts down digestion
Kidney 2 Increases renin secretion Increases blood pressure
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Distribution and effects
 Activating a-adrenoceptors generally contracts smooth
muscle (except gut)
 Activating b 2-adrenoceptors relaxes smooth muscle
 Activating b 1-adrenoceptors contracts cardiac muscle
 b 2-Adrenoceptors predominate in the airways
 b 1- Adrenoceptors predominate in the heart
 Receptors are distributed differently in different organs and
tissues
 Receptor-selective drugs act selectively at different organs
and tissues
3. Chemical messengers Sec. alcohol
General structure of catecholamines

Alkylamine
Catechol
Amine
Noradrenaline - neurotransmitter
Adrenaline - hormone
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4. Biosynthesis
Notes
 Pathway controlled by regulation of tyrosine hydroxylase
 Inhibited by noradrenaline - feedback control
Inactivation of Catecholamines
1. Reuptake into the adrenergic nerve ending, stored into

storage granules until sympathetic nerve stimulation.
2. Enzymatic metabolism: Two principle enzymes involved
in Catecholamines metabolism:
a) Monooxidase (MAO), acts via oxidative deamination of
catecholamines
b) Catechol-O-methyltransferase (COMT), methylates the
meta hydroxyl group of catecholamines.
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5. Metabolism of noradrenaline
MAO = Monoamine oxidase

COMT = Catechol O-methyltransferase
6. Transmission process
.
Target
. Target cell
Target
. .
cell cell
. nerve signal
. .
nerve signal
signal
Vesicles fuse and release transmitter

Receptor binding and new signal
. .
Target Target Target
cell
cell . cell
. .
Neurotransmitter departs receptor
Neurotransmitter repackaged or
Neurotransmitter reabsorbed
metabolized
By active transport
Receptor Transport protein

. Vesicle containing
noradrenaline
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6. Transmission process
Presynaptic Control
•Presynaptic receptors control release of noradrenaline
•Prostaglandins, acetylcholine and noradrenaline affect release
•Active cholinergic nervous system inhibits adrenergic activity
Ach Prostaglandins
Cholinergic receptor
Presynaptic adrenergic receptor
Prostaglandin receptor
NA
Postsynaptic adrenergic receptor
NA
Activation of target receptor
reduces noradrenaline release
NA Noradrenaline
Smooth muscle
7. Drug targets
5 .
Tyr
1
. . 3 . 4
6
Metabolites
2 .
.
7
Noradrenaline Transport protein

Adrenergic receptor Presynaptic receptor
1. Enzymes in the biosynthesis of noradrenaline

2. Vesicles carrying noradrenaline
3. Exocytosis of vesicles with cell membrane
4. Adrenergic receptor
5. Transport protein for noradrenaline
6. Metabolic enzymes
7. Presynaptic receptors © Oxford University Press, 2013
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8. Adrenergic binding site
TM6
Asn-293
Phe-290
C NH2
..O..
H
H
H O
+ H
Ser-207 . H O N
.. .
O
CH 3
..
Ser-204 O .. H O
H
CO2
TM5 TM3
Asp-113
9. Structure-Activity Relationships
Alcohol
Phenol
Aminium ion
Phenol
Notes
•Phenol groups form H-bonds to binding site (especially b-
adrenoceptors)
•meta-Phenol can be replaced with other hydrogen bonding
groups
•Alcohol forms a hydrogen bond to the binding site
•Aminium ion forms an ionic bond to the binding site
•N-Alkyl groups affect target selectivity
•Larger N-alkyl groups lead to selectivity for b-adrenoceptors
•Aromatic ring forms van der Waals interactions with the binding
site © Oxford University Press, 2013
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Stereochemistry of NE and Epi
 There is a chiral carbon.

 There are two optically active isomers: (-) and (+)
 (-) Epinephrine is more active than (+) Epinephrine.
Why?
 Different binding
 (-) isomer fits with receptor via points of interaction,
more than that of (+).
 Hence, the (-) isomer has higher affinity and activity.
(-) Epinephrine
(+) Epinephrine
Binding of (-) and (+) isomers
The (-) isomer fits with receptor via points of

interaction, more than that of (+).
Hence, the (-) isomer has higher binding affinity.
(-) isomer is more active than (+)
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Adrenergic Drugs
 The drugs that act on the peripheral sites of the sympathetic
nervous system are collectively named adrenergic drugs.
 They act via either enhancing or inhibiting the sympathetic
activity.
Sympathomimetic Drugs
According to the mechanism of action, sympathetic drugs

may be classified into :
1. Direct acting Sympathomimetics.
(interact directly with adrenergic receptors)
2. Indirect acting Sympathomimetics.
(initiate the release of NE from adrenergic nerve terminal
which activate the receptor or inhibit its uptake mechanism)
3. Mixed function adrenergic agonists
(interact directly with the receptor and act indirectly by
increasing the conc. of NE at the receptor site)
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Prototype of direct-acting sympathomimetics:

Norepinephrine, epinephrine and isoproterenol
They are phenylethylamine derivatives that contain the
appropriate substituents.
Also, they are Catecholamines.
NE and Epi are natural NT and neurohormone.

Isoproterenol is a synthetic compound.
Epinephrine (Adrenaline) as a drug

Chemical name:
(-) 1-(3,4-Dihydroxyphenyl)-2-
methylaminoethanol
Salts:
Present as acidic salt: HCl
Action & Structural features:
Epinephrine has both α and β-effects.
No selectivity (α and β) due to a secondary amine with a
methyl substituent
Direct adrenergic agonist, due to the presence of the
catechol OHs, the β-OH and a secondary amine group.
 The amine function is affected by MAO.
 Short duration of action
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Structural features
Catechol nucleus is rapidly affected by COMT.
Short duration of action and oral inactivity.
Highly polar molecule: decreased penetration into the eye
* Because of the catechol nucleus, it is oxidized easily and

darkens slowly on exposure to air (chemical instability)
due to formation of inactive quinone.
* Thus, solutions are stabilized by adding reducing

agents as ascorbic acid.
Structural features
There is a chiral carbon.

There are 2 isomers
The levorotatory isomer of epinephrine is more active
At physiological pH (7.4), NE and Epi are found to exist in

more than 95% in the cationic form in which nitrogen is
protonated.
pKa of epinephrine = 8.55
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Uses of Adrenaline
Adrenaline used for
 Severe anaphylactic shock
 Vasoconstrictor in patient with hemorrhage.
• fast acting, but short acting
• unsuitable for long term medication
• cardiovascular side effects
 Vasoconstrictor in nasal decongestion.
 Increase the activity of local anesthetics.
 a limited use in case of bronchial asthma and heart block
Disadvantages
 Short duration. (rapid metabolism)
 Not taken orally
Norepinephrine
 Presence of the β-OH and the catechol OHs and the

amine, so optimal direct action.
 It is a 1ry amine; so, α-adrenergic activity. Mainly α
agonist activity.
 Metabolically vulnerable to MAO and COMT, so short
duration of action and no oral activity.
 Short acting: Unsuitable for long term medication
 Chemically unstable where photo-oxidation is possible,
so protect from light and OH- .
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Phenylephrine HCl
(-) 1-(3-hydroxyphenyl)-2-(methylamino)
ethanol
• α-agonist.
• Duration of action twice epinephrine.
• Used as nasal decongestant and to maintain blood
pressure.
• Effective orally and by injection.
Isoproterenol = Isoprenaline
 (-) 1-(3,4-dihydroxyphenyl)-2-
(isopropylamino)ethanol
 β-adrenergic agonist
 Shows selectivity for b-adrenoceptors over α receptors

• Bulky isopropyl group introduces b-selectivity why?
• But, No selectivity between b-subtypes (β1 and β2)
• Cardiovascular side effects
 a non selective β-adrenergic agonist, it acts equally on:
 β1 receptors resulting in cardiac stimulation.
 β2 receptors resulting in bronchodiltation.
 This non selectivity reduce utility for treatment of
bronchial asthma.
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β-Adrenergic Agonists
 The receptor has a larger lipophilic binding pocket

adjacent to the amine-binding aspartic acid residue than
do the receptors.
 The bulkiness of the alkyl group appears to hinder the
interaction of the drug with the α-receptor, but it has no
inhibition on β-receptors.
 How would you get a selective β2-agonist ???
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β2-Adrenergic Agonists
Structural modification in isoprenaline to enhance the β2-
agonist selectivity
1) Insertion of C2H5- at α-carbon atom.
2) Replacement of the isopropyl moiety with tert-butyl.
3) Replacement of the catechol moiety by resorcinol.
4) Replacement of the meta -OH by CH2OH.
result in β2-agonists used mainly as bronchodilator.
B2-Adrenoceptor
•Not recognised by COMT
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7. Salbutamol (Albuterol)
Hydroxymethylene
3-hydroxymethyl-4-hydroxy-a-[(t- t-Butyl group
butylamino)methyl]benzyl alcohol
Notes
•Hydroxymethylene group retains b 2-agonist activity
•Forms a hydrogen bond to the target receptor
•OH shifted from aromatic ring by one bond length
•Not recognised by COMT
•Same potency as isoprenaline
•2000 times less active on the heart
•4 hours duration of action
•Market leader for the treatment of asthma
8. Levalbuterol
Notes
•R-Enantiomer of salbutamol
•R-Enantiomer is 68 times more active than the S-enantiomer
•Example of chiral switching
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9. Salmefamol
27/12
Extension
Notes
•N-Arylalkyl group added
•Methoxy group interacts with a polar region of the binding site
•Extra binding interaction
•1.5 times more active than sulbutamol
•Longer duration of action (6 hours)
10. Salmeterol
Polar group
Hydrophobic Hydrophobic
Notes
•Longer lasting agent
•Used for nocturnal asthma
•Increased lipophilicity
•Binds more strongly to tissue in vicinity of the receptor
•N-Substituent is lengthened
•2x more active than salbutamol
•Longer duration of action (12 hours)
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SAR of Direct-acting Adrenergics

A. Aromatic ring
 Catechol hydroxyl groups in the meta- and para-
positions of the aromatic ring, relative to the
phenethylamine moiety.
 The catechol OH groups are more important for β-
activation (β-agonist activity) than for α-activity. (form H-
bonds to binding site (especially β) (H-bond)
 So, removal of one of them results in loss of β-activity.
(but keeping α-agonist activity)
 When OH groups are removed, compound retains α
affinity. © Oxford University Press, 2013

A. Aromatic ring
 meta-OH can be replaced with other hydrogen bonding

groups,CH2OH, CH2CH2OH, NH2 , NHMe, NHCOR, NMe2 , and
NHSO2R;
 Replacement of catechol with resorcinol afford compound
with longer duration, why? (resorcinol is not a substrate
for COMT), and enhances b2-selectivity
Aromatic ring forms van der Waals interactions

with the binding site
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B) Ethyl part (the spacer)
Two C-atoms separating the amino from the

aromatic ring provide optimal activity.
 β-Hydroxyl group on the ethylamine portion of
the molecule enhances the activity since it is
involved in binding of the compound with
receptor (direct action).
 Alcohol forms a hydrogen bond to the binding
site © Oxford University Press, 2013

 Stereochemistry of the –OH is important, since it is

involved in the binding of the compound with the
receptor.
 Proper stereochemistry of the b–OH group
enhances the activity of NE and other
catecholamines since it is involved in the binding of
the compound with the receptors.
 R(-)NE fits with the receptor better than the other
enantiomer. © Oxford University Press, 2013
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 Alkyl substitution on the α-carbon atom increases
the duration of action of the phenethylamine
agonists by making the compound resistant to
metabolic deamination by MAO.
 Greater CNS activity – indirect activity
 The Introduction of a chiral Center
 The presence of α-ethyl group enhance β2-agonist
activity with less cardiac stimulation.
 α-Methyl substitution : addition of an α-methyl group
(e.g. α-methyl noradrenaline) increases α2 - receptor
selectivity

C) The amine part
 Amino group is essential for binding.

(protonated)
 ammonium ion (after protonation) forms an
ionic bond to the binding site(pH)
Amino group: primary or secondary Not tertiary
or 4 ry.
 In case of 2ry amines, N-alkyl substitution
affect selectivity (α and b)
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C) The amine part
 Large substituents on the amino group also

protect the amino group from undergoing
oxidative deamination by MAO.
Increasing the size of the alkyl groups, enhances
the β-affinity & reduce α-affinity.
 isopropyl or tert. Butyl are named β-directing
groups
 tert. Butyl is a β2-directing groups
SAR of Direct-acting Adrenomimetics
 Catechol and Aromatic ring

 Distance and alcoholic group
 Amine and N-alkyl substituent
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Indirect Acting Sympathomimetics

Indirect adrenergic drugs are taken up by the pre-synaptic
neurons. where they:
• Stimulate release of NE from adrenergic nerve terminals,
which activates the receptors
• Inhibit reuptake mechanism of neurotransmitter
Amphetamine
2-Amino-1-phenyl-propane
• The prototype of this class of adrenergics.

• It is available as HCl and sulfate salts.
• It stimulate the release of norepinephrine.
• No direct action
• No phenolic OHs, no alcoholic OH … no direct action
• The absence of phenolic and alcoholic OH group
increase the lipophilicity, so penetrate the BBB giving
CNS activity.
• CNS stimulant and central appetite suppressant effects
• Uses: Narcolepsy / Attention deficit disorders / obesity.
• There is a chiral carbon.
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Methamphetamine
Chemical name: ……………………
think about it !!!!
• N-methyl derivative of amphetamine

• Structure: No catechol OHs, no beta-OH, an alpha
methyl, N-methyl.
• Discuss the effect of each??
It has central effects more than amphetamine

Meth is an abused drug.
Chemistry of indirect acting

Structural Features
 Phenylethylamine structure
 Absence of catechol OH groups results in:
 Increase oral absorption.
 COMT has no effect. Increase duration of action.
 Increase lipophilicity so pass through blood-brain barrier.
 Phenyl group may be replaced by other systems as cyclo /
alkyl group.
 Presence or absence of β-hydroxyl group.
 If present, stereochemistry is not important.
 Its absence provides more lipophilic agents with central
stimulation
 a-CH3 in the phenethylamine structure provides more
resistance to MAO.
 The amino nitrogen: primary, or secondary (small alkyl gr).
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Dual Function Adrenomimetics
• Mixed means Direct and Indirect actions.

• direct action on the adrenergic receptors.
• indirect effect on the release of NE from the storage site
•The prototype of this group is the natural alkaloid
ephedrine.
• Ephedrine has two (asymmetric) chiral carbons: so four

stereoisomers (4 optically active isomers that exist as two
pairs of enantiomers.)
• Used by injection and orally.
 Used as vasopressor, nasal decongestant.
 cardiac stimulant in hypotensive conditions
 In allergic disorders, colds, nasal congestion
 bronchodilator in asthma
 CNS stimulant in narcolepsy © Oxford University Press, 2013
Pseudoephedrine
(+)-Threo-2-(methylamino)-1-phenyl-1-
propanol
• Pseudoephedrine is the threo-diastereoisomer of

ephedrine
• has virtually no direct activity
• Mainly indirect action.
• widely used as nasal decongestant.
Phenylpropanolamine
• Mainly indirect action
• N-desmethyl analog of ephedrine. Lacking N-methyl group
• So, no β2 agonist activity, no bronchodilator as ephedrine
• Slightly less lipophilic, low CNS activity.
• It is nasal decongestant in OTC cold drugs
• It is an appetite suppressants (anorexiants)
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Mixed Function Adrenomimetics:

Structural Features
1. Absence of phenolic OH groups leads to increase oral

absorbance, increase lipophilicity and a CNS effect. Also, it
is not a substrate for COMT, similar to indirect adrenergic
agonists.
2. The presence of b-hydroxyl group brings similarity to
other catecholamines acting directly on adrenergic
receptors
3. Presence α-methyl group provides resistant to MAO and
hence longer duration.
4. ephedrine is less polar than the catechol derivatives, so it
can cross blood-brain-barrier, so used as CNS stimulant.
Imidazoline Adrenergic Agonists

 They act on α1- and α2-receptors.
 Those that act on α1- receptors have vasoconstrictor
activity
 They are used as nasal decongestive agents and eye
drops.
 Is there any similarity with the phenylethylamine structure ?

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Imidazolines: SAR
 They contain one carbon bridge between C-2 of the

imidazoline ring and a phenyl moiety. Therefore, the
skeleton of the phenethylamine is present.
 Lipophilic substitution on the phenyl group ortho to the
methylene bridge appears to be required for α1- and α2-
affinity.
 Bulky lipophilic substituents at meta or para position
diminish affinity for α2- receptors and thus provide
selectivity for α1-receptors.
a2-Agonists
• Stimulation of central a2-receptors (agonist effect) plays a
regulatory role in the release of NE.
• Thus, compounds possessing central a2-receptors agonist
activity could be used for management of hypertension.
• The imidazoline derivative, clonidine, is an important a2-
agonist.
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Clonidine Hydrochloride
2-(2,6-Dichloroanilino)-2-imidazoline
It is an imidazoline dr.
• The chlorine atoms : lipophilic; compound acts centrally at
a2-receptors.
• The compound has some peripheral a1-agonist activity.
• There is no methylene bridge but an -NH- which makes a
guanidine moiety.
• The imidazoline nucleus is not essential for central a2-
agonist activity
• the phenyl ring required at least one ortho chlorine or
methyl group
• the bulky ortho-chlorine groups does not permit a coplanar
conformat ion of the two rings
α-Adrenergic Blockers
• Types and classification of α-Blockers:
– Non-Selective α Blockers
– Selective α-blockers include α1 and α2 types
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Non-selective α-blockers
1. Non-selective competitive α1 adrenergic
receptor antagonists.
•Have both α1 and α2 blocking activity.
•Used as vasodilators and to treat hypertension.
•They are similar to the imidazoline 1-agonists, but
does not have the lipophilic substituents required for
agonist activity.
Phentolamine
Non-selective irreversible
α1 blockers
• Phenoxybenzamine is a haloalkylamine that
blocks α1- and α2- receptors irreversibly.
• Form covalent bond– long lasting
• Aziridinum formation
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Selective Quinazoline α1-Blockers

• Quinazoline Selective α1-blockers are used
to treat high blood pressure, prostatic
benign hyperplasia.
Prazosin Terazosin
doxazosin
Quinazoline α1-Blockers, SARs
• 4-amino group on the

quinazoline ring is important
for α1-receptor affinity.
• Type of acyl group has a
significant effect on the PK
properties.
• Piperazine moiety can be
replaced with other
heterocycles (e.g. piperidine)
without loss of affinity.
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β-Adrenergic Antagonists
Development
Lead compound
Isopropyl group
Isoprenaline
•Isoprenaline is a b-agonist rather than antagonist

•Shows selectivity for b-adrenoceptors
•N-Isopropyl group is responsible for selectivity
Variation of the meta-phenol group

Notes
•Phenol is an important binding group (HBD or HBA)
•Susceptible to metabolism
•Replace with a different hydrogen bonding group
Carboxylic acid Ester Amide
Inactive b 2-Antagonist b 2-Antagonist
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Converting an agonist to a partial agonist
Isoprenaline Dichloroisoprenaline Pronethalol

(agonist) (partial agonist) (partial agonist)
Notes
•Phenol groups are not required for antagonist activity
•Add extra binding groups to convert an agonist to an antagonist
•Hydrophobic groups form extra van der Waals interactions
•Structure binds but produces a different induced fit
•Act as partial agonists
- weakly activate receptors
- block natural messenger
Converting a partial agonist to an antagonist

Spacer
Ether
Pronethalol •Introduce spacer Propranolol

(partial agonist) (chain extension) (antagonist)
•Vary substituent position
Notes on propranolol
•Spacer introduced - chain extension strategy
•Substituent is positioned at a different part of the ring
•Ether group acts as a hydrogen bond acceptor (extension strategy)
•10-20 times greater antagonist activity
•Used clinically as a racemate
•S-Enantiomer is the active enantiomer
•Aryloxypropanolamine structure
•Blocks b 1 and b 2 adrenoceptors
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6. Synthesis of aryloxypropranolamines
Notes
•Synthesis allows variation of aromatic rings and N-substituents
•Racemic products are formed
7. SAR on aryloxypropanolamines
Substitution
Propanolamine group lowers activity
Amine
Ether
N-Alkyl
Alcohol
group
Aryloxy group Naphthalene
Notes
•Ether acts as a hydrogen bond acceptor
•Ether can be replaced with an alternative HBA
•Alcohol is essential as a hydrogen bonding group (stereochemistry)
•Amine is ionised and forms an ionic bond with the binding site
•Amine must be secondary
•Naphthalene is replaceable with heteroaromatic rings
•Branched N-alkyl group fits a hydrophobic pocket
•Extension of N-alkyl group with N-arylethyl group is beneficial
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8. Variation of the naphthalene ring
Propranolol Pindolol Timolol
•Causes less bradycardia •Protective value in

than other beta blockers reducing the recurrence
•May cause less coldness rate of myocardial
of the extremities infarction
•Also used in treatment of
glaucoma and migraine
Second-generation b-blockers
Notes
•First-generation b-blockers such as propranolol act against both

b 1 and b 2-adrenoceptors
•Cannot be used with asthmatic patients
•Antagonism of b2-adrenoceptors constricts airways
•Second-generation b-blockers are designed to be b1 -selective
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9. Second-generation b-blockers
Acebutolol Atenolol Metoprolol Betaxolol

Notes
•Selective cardiac b 1-antagonist
•Amide group important for selectivity
•More polar
•Less CNS side effects
•Used for the treatment of angina and hypertension
9. Second-generation b-blockers
binding interactions
•Amido group must be para for b 1-selectivity
•Extra hydrogen bonding interaction takes place
•Not possible with b 2-adrenoceptor
O N O N
H2 H2
OH OH
O
H3C N
H
HN CH3
H H
X X
para substitution meta substitution

Extra H-bonding interaction
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Mixed α and β-Blockers

Labetalol
β-Blocker > α-Blocker.

Used to treat Hypertension.
Carvedilol
• β-Blocker > α-Blocker.
• Used to treat Hypertension and Congestive Heart Failure
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Synthesis of Phenylephrine
Synthesis of Carbachol
 It is made by reacting 2-chloroethanol with phosgene, which

forms 2-chloroethyl chloroformate.
 Upon reaction with ammonia, it turns into the corresponding
amide,
 which is further reacted with an equimolar quantity of
trimethylamine, giving carbachol.
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‫‪Al-Esraa University College‬‬
‫‪Pharmaceutical Chemistry II‬‬
‫‪Dr. Hany Hafez‬‬
‫قسم الصيدلة – كلية اإلسراء‬

‫المرحلة الرابعة‬
‫الكيمياء الصيدلية ‪2‬‬
‫المحاضرة الخامسة و السادسة‬
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
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).
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.
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
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.
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.
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)
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)
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.
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.
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
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.
 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.
 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
THE BODY’S OWN
‘OPIOIDS’
ENKEPHALINS
THE BODY’S PAINKILLERS
Met-Enkephalin
H-Tyr-Gly-Gly-Phe-Met-OH
Leu-Enkephalin
H-Tyr-Gly-Gly-Phe-Leu-OH

NOTES – ENKEPHALINS
 Endogenous peptides acting as neurotransmitters in
brain
 Enkephalin - Greek for ‘in the head’
 Bind to opioid receptors with some selectivity for
delta receptors ()
 Approximately 15 other endogenous peptides of 5-26
AA’s (endorphins and enkephalins).
 All contain Met or Leu enkephalin at C-terminus
 Inactived by peptidase enzymes in vivo (orally
inactive) - hydrolysed between Tyr and Gly
H-Tyr-Gly-Gly-Phe-Met-OH
SAR
 Tyrosine essential for activity (phenol group and N)
 Phenol group of Tyr thought to be equivalent to

phenol group of morphine
 Tyr nitrogen thought to be equivalent to morphine

nitrogen
 Aromatic ring of Phe important (additional

interaction)

Additional
Interaction
Phenol Phenol
Amine
Amine
ANALOGUES
AIM
To synthesise analogues which are stable to
peptidases and which would be orally active
STRATEGY
Replace non-essential amino acids with unnatural
AA’s or D-AA’s to make enkephalin unrecognisable
to peptidase enzymes

EXAMPLES
H-(L-Tyr)-(D-AA)-Gly-(NMe-L-Phe)-(L-Met)-OH
unnatural
amino acids
(N,N-Diallyl-L-Tyr)-aib-aib-(L-Phe)-(L-Met)-OH
unnatural
amino acids
aib = -aminobutyric acid
Neuron 1 Neuron 2
BRAIN
Pain Signal

Neuron 1 Neuron 2
BRAIN
Pain Signal
Neuron 1 Neuron 2
BRAIN
Pain Signal

Neuron 1 Neuron 2
BRAIN
Pain Signal Pain Signal
Neuron 1 Neuron 2
BRAIN

Neuron 1 Neuron 2
BRAIN
Neuron 1 Neuron 2
BRAIN

Neuron 1 Neuron 2
BRAIN

MORPHINE
Structure
1923
HO
O MORPHINE
NMe
HO
Potential Binding Groups
Functional groups are present capable of

forming ionic, hydrogen bond and van der
Waals interactions
Carbon skeleton – capable of forming van

der Waals interactions HO
O
NMe
HO

Structure Activity Relationships
• Mask or remove a functional group

• Test the analogue for activity
• Determines the importance or otherwise
of a functional group for activity
Structure Activity HO
Relationships
O
Phenol NMe
HO
Aromatic
ring
Ether
Alkene
Alcohol
Amine

SAR - The phenol moiety
RO
R=H Morphine
R=Me Codeine
H NMe
H
HO
Codeine 20% active (injected peripherally)

0.1% active (injected into brain)
Notes
 Codeine is metabolised in the liver to morphine.

 The activity observed is due to morphine.
 Codeine is used for mild pain and coughs
 Weaker analgesic but weaker side effects.
Conclusion
 Masking phenol is bad for activity

RO
R=Ac 3-Acetylmorphine
Decreased activity
H NMe
H
HO
•Acetyl masks the polar phenol group

•Compound crosses the blood brain barrier more easily
•Acetyl group is hydrolysed in the brain to form morphine
SAR - The 6-alcohol
HO
R=Me Heterocodeine
5 x activity
H NMe
H
RO

SAR - The 6-alcohol
HO HO HO
O O O
NMe NMe NMe
HO O
•Activity increases due to reduced polarity

•Compounds cross the blood brain barrier more
easily
•6-OH is not important for binding © Oxford University Press, 2013
SAR - The 6-alcohol
HO
R=Ac 6-Acetylmorphine
Increased activity (4x)

O
H NMe
H
RO
•Acetyl masks a polar alcohol group making it easier to
cross BBB
•Phenol group is free and molecule can bind immediately
•Dependence is very high
•6-Acetylmorphine is banned in many countries © Oxford University Press, 2013
SAR - The 6-alcohol and phenol
RO
R=Ac Heroin
Increased activity (2x)

O
H NMe
H
RO
•Increased lipid solubility
•Heroin crosses the blood brain barrier more quickly
•Acetyl groups are hydrolysed in the brain to generate
morphine
•Fast onset and intense euphoric effects © Oxford University Press, 2013
SAR - Double bond at 7,8
HO
Dihydromorphine
O
Increased activity
H NMe
H
HO
The alkene group is not important to binding

SAR - Nitrogen
HO
No activity
O
H CHMe
H
HO
Nitrogen is essential to binding
SAR - Methyl group on nitrogen

NR= NH Normorphine
HO Reduced activity (25%)
+
NR= NMe
-
O O
No activity
H NR NR= N+Me2
H No activity
HO
•Normorphine is more polar and crosses the BBB slowly
•Ionised molecules cannot cross the BBB and are inactive
•Ionised structures are active if injected directly into
brain
•R affects whether the analogue is an agonist or an
antagonist © Oxford University Press, 2013
SAR - Stereochemistry
HO HO
O O
NR H NR
H H
H
HO HO
Mirror image of morphine 10% activity

No activity
Changing the stereochemistry is detrimental to

activity © Oxford University Press, 2013
SAR - Important binding interactions
HBD or HBA
HO
van der Waals
H NMe
H
HO Ionic
(N is protonated)

PHARMACOPHORE
VDW
HBD/HBA
Ionic
PHARMACOPHORE
VDW
HBD/HBA
Ionic

PHARMACOPHORE
VDW
HBD/HBA
Ionic
PHARMACOPHORE
2.800Å
VDW
HBD/HBA
7.198Å
4.641Å
Ionic

PHARMACOPHORE
2.800Å
19o VDW
HBD/HBA 149.3o
7.198Å
4.641Å
11.3o
Ionic
OPIOID RECEPTORS
2020

Receptor Theories
Beckett-Casy hypothesis
* Single opioid receptor interacts with morphine
* Ionic binding region (CO2-) interacts with positive N+
* Hydrophobic binding region interacts with aromatic ring
* Hydrogen bonding region interacts with phenol
* Hollow region accepts carbon bridge (C-15 and C-16)
Ionic binding region
vdW binding region
Hydrogen bond
binding region
RECEPTOR

SCAFFOLD
SCAFFOLD
RECEPTOR

Receptor Theories
Drawbacks with the Beckett-Casy hypothesis
* Ethylene bridge is not important in some analgesics (fentanyl)
* No account for extra binding regions found by extension
* Does not explain different SAR results (e.g. meperidine vs morphine)
* Does not explain mixed antagonist/agonist properties
Receptor Theories
Multiple Analgesic Receptors
* Three different analgesic receptors (mu, kappa and delta)
* Binding sites for all three receptors contain ionic, hydrogen

bonding and hydrophobic regions as proposed by Beckett-Casy
* Activation of all three produce analgesia, but differ in other

effects
* All three interact with morphine
* Potential to target drugs selectively

Mu Receptor ()
* Morphine binds strongly
* Activation produces analgesia plus side effects

(respiratory depression, euphoria, addiction)
* G-Protein coupled receptor
* -Receptor subtypes have been proposed which may allow

separation of analgesia from side effects
* -Receptors related to all sources of pain stimuli
Kappa Receptor ()
* G-Protein-coupled receptor
* Morphine binds less strongly
* Receptors related to non-thermal pain induced stimuli
* Activation produces analgesia plus sedation
* Potential target for safe analgesics (compounds acting as

agonists at , antagonists at and no activity at the receptor)
* But psychotomimetic side effects

Delta Receptor ()
* Morphine binds strongly
* Receptor for enkephalins
* Activation produces analgesia plus some side effects
* G-Protein-linked receptor
*  receptors related to pain induced stimuli from all sources
Main effects of opioids at opioid receptors
Blue = Agonist (Blue) = Partial agonist Red = Antagonist

Agonists vs Antagonists
* Why should small changes in structure (e.g. N-methyl to N-

allyl) change an agonist to an antagonist at a specific receptor?
* Proposed that specific receptors have additional hydrophobic

binding regions which lead to agonist or antagonist activity.
DRUG DESIGN OF OPIOID

ANALGESICS

Aims of opioid drug
design
• To maintain activity
• To lower side effects
• To increase oral activity
Four classical drug design strategies were

applied to obtain novel analgesic structures:
I. Peripheral modifications:
1. Variation of substituents
2. Drug extension
II. Simplification (drug dissection)
III. Rigidification

Extension
– Add extra binding groups
– Find extra binding regions
– Increase activity
– Decrease side effects
• Extension at position 14
HO
O
NMe
HO 14

• Extension at position 14
HO
OXYMORPHINE
2.5 x activity
O
NMe
OH
O
Possibly an extra hydrogen bonding interaction with

the receptor through the 14-OH group
• Extension - N-Substituents
HO
O
NR N-Substituted morphines
HO

HO
Analogues
O
NR
HO
R= Me Et Pr Bu Amyl, hexyl CH2CH2Ph
Activity drops No Activity 14x Activity

Activity restored
Conclusion
Phenethyl substituent reaches a hydrophobic binding region


Analogues
HO
O
R= CH2-CH=CH2 or CH2
NR
HO
•Act as antagonists!
•Bind to receptors
•Fail to activate receptors
•Useful to counteract morphine overdoses
•Useful for treating drug addiction to morphine or heroin
Examples of antagonists
HO HO
O O
N N
OH
O
O
Naloxone
Naltrexone
•Potent antagonist •8 x more active than

•2 x more active than naloxone as an antagonist
nalorphine •Given to wean drug addicts
off morphine or heroin
Examples of antagonists with agonist activity

HO
Nalorphine
O
N
HO
•Antagonist
•Used to treat morphine overdose
•Weak agonist as well!
•Indication of multiple opioid receptors
•Antagonist at some, agonist at others
•Non-addictive analgesic
•First indication of a safe opioid analgesic
•Hallucinogenic side effects

Examples of antagonists with agonist activity
HO
O Nalbuphine
N
OH
HO
•Similar activity to morphine

•Low addiction liability
•No psychotomimetic effect
•Not orally active
Binding Regions
H-Bond
Hydrophobic
Antagonist hydrophobic binding region
Ionic
Agonist hydrophobic binding region

Binding Modes for Morphine
H-Bond
HO
Hydrophobic
Extra hydrophobic
regions
O
N Me
Ionic ..
HO
Methyl group of morphine incapable of reaching either of the extra

hydrophobic regions
Binding Modes for N-Phenethylmorphine
HO
O
N
..
HO
Pure agonist with enhanced activity

Binding Modes for N-Phenethylmorphine
H-Bond
HO
Hydrophobic
O
N
Ionic ..
HO
•Aromatic ring pushed beyond antagonist

hydrophobic binding region
•Correct distance to bind to agonist hydrophobic
binding region
Binding Modes for N-Allylmorphine
H-Bond H-Bond
Hydrophobic HO
Hydrophobic
HO
O O
N N
Ionic ..
Ionic ..
HO HO
•Allyl group binds well to the antagonist region

•Allyl group forms a weak interaction with the agonist region
•Antagonist with weak agonist properties

Simplification Strategies
• Remove non-essential functional groups
• Remove excess rings
• Remove excess asymmetric centres
Properties of simplified analogues

• Easier, quicker and cheaper to make
• May increase or decrease activity
• May interact differently with receptor
• May increase or decrease side effects

HO
O D
NMe
HO
Remove excess functional groups and ring D
Morphinans
HO
NMe
Levorphanol

Morphinans
HO
NMe NMe
Levorphanol N-Methylmorphinan
•5x activity 20% activity (no phenol)

•Increased side effects
•Orally active
•Longer duration
•Less metabolism in liver
Morphinans
HO HO
Ph
N N
Levallorphan N-Phenethyl levorphanol
Antagonist 15 x activity of morphine

5 x nalorphine

Morphinans
HO
Butorphanol
N
OH
Antagonist with agonist properties
Not orally active
Morphinans
1) Morphinans are more potent and longer

acting than their morphine counterparts, but
also have higher toxicity and comparable
dependence characteristics
2) Changes carried out on morphinans have

the same biological effect as those carried out
on morphine. Implies the same receptor
interactions and binding
3) Simpler molecules and easier to synthesise

Morphinans
HO
A
B
E
NMe
C
REMOVE RING C & D
6,7-Benzomorphans
HO
A
B
E
Me NMe
Me

6,7-Benzomorphans
HO HO
NMe Me NCH2CH2Ph
Me
Me Me
Metazocine Phenazocine
Same activity 4 x activity
as morphine of morphine
6,7-Benzomorphans
HO HO
NMe Pr NMe
Pr
Me Me
Analgesia + Analgesia + suppression of

dependence withdrawal symptoms

6,7-Benzomorphans
HO
Me
N Me
Pr
Me
Pentazocine
•1/3 analgesic activity (antagonist properties)

•Short duration
•Low addiction liability
6,7-Benzomorphans
Conclusions
1) Rings C and D are not essential for analgesic activity
2) Analgesia and addictiveness are not necessarily co-

existant
3) Clinically useful compounds with reasonable
analgesic activity, less addictive liability and tolerance
4) Simpler to synthesise
5) Interact with target binding sites in the same way as

morphine

6,7-Benzomorphans
HO
A
B
E
NMe
REMOVE RING B
4-Phenylpiperidines
HO
A
E
NMe

4-Phenylpiperidines
HO
HO
A
=
R
E
R NMe
N
Me
4-Phenylpiperidines
•20% activity of morphine

CO2Et •Side effects and less sedation
•Rapid onset and short duration
•Used in child labour
•Less likely to affect baby’s breathing
N
Me
Meperidine or pethidine

4-Phenylpiperidines
Notes
 Phenol group is not necessary for activity
 Ester group is a binding group that is not present in
previous structural classes
 N-Allyl or cyclopropyl groups show no antagonist
properties
 Implies different receptor interactions
 More flexible molecules may allow different binding
modes
 Very easy to synthesise
4-Phenylpiperidines
E
R NMe
Open the piperidine ring E

A
R R’ NMe
Methadone
Asymmetric centre
A A Me
*
Me
= NMe2
Ph
Et NMe2 COEt
Ph C
(R) 2 x activity of morphine
O (S) Inactive

Methadone
Notes
•Discovered in Germany during Second World War
•Useful analgesic and orally active. Slightly sedative
•Side effects (depresses respiration, dependence potential)
•Has less severe emetic and constipation effects.
•Minimal euphoric effect and less severe withdrawal

symptoms
•Used as a substitute for morphine or heroin to treat addicts
•Flexible molecule - different binding mode from morphine


Rigidification Strategy
• Less flexible structures
• More active if active conformation is retained
• Possibly less side effects
• Better oral absorption
• Less easy to make
Thebaine
MeO
O
NMe
MeO
Inactive but useful starting material for the synthesis of rigid opiates

Synthesis of orvinols
MeO O MeO
O Diels O
Alder
NMe NMe
MeO MeO
R O
MeO HO
R’MgBr O O
Grignard KOH
NMe NMe
Ethylene
glycol
MeO MeO
R OH R OH
R’ R’
Etorphine
HO
NMe
MeO
Me OH
Pr
•10 000 x more active than morphine

•20 x affinity for receptor
•300 x penetration of BBB
•Used as a sedative for big game animals

Diprenorphine
HO
O
N
MeO
Me OH
Me
Antagonist
100 x more active than nalorphine

Buprenorphine (1968)
HO
O
N
MeO
Me
OH
Me Me
Antagonist with agonist properties
Buprenorphine (1968)
Properties (wrt morphine)
•Clinically useful analgesic

•No euphoria or addiction liability
•Low dependence potential
•Lower respiratory depression
•Sublingual administration (avoids liver metabolism)
•Longer duration
•Side effects (drowsiness, nausea and dizziness)
•Dissociates slowly from the receptor

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10/11/2022

© Oxford University Press, 2013

Ach = Acetylcholine Smooth muscle

2. Adrenergic receptors (adrenoceptors)

© Oxford University Press, 2013

2. Adrenergic receptors (adrenoceptors)

2 Smooth muscle relaxation Dilates and open airways

Arteriole smooth muscle 2 Smooth muscle relaxation Dilates arterioles and

Kidney 2 Increases renin secretion Increases blood pressure

© Oxford University Press, 2013

2. Adrenergic receptors (adrenoceptors)

3. Chemical messengers Sec. alcohol

General structure of catecholamines

© Oxford University Press, 2013

1. Reuptake into the adrenergic nerve ending, stored into

© Oxford University Press, 2013

MAO = Monoamine oxidase

Vesicles fuse and release transmitter

Receptor Transport protein

© Oxford University Press, 2013

Noradrenaline Transport protein

1. Enzymes in the biosynthesis of noradrenaline

8. Adrenergic binding site

© Oxford University Press, 2013

Stereochemistry of NE and Epi

 There is a chiral carbon.

© Oxford University Press, 2013

Binding of (-) and (+) isomers

The (-) isomer fits with receptor via points of

© Oxford University Press, 2013

According to the mechanism of action, sympathetic drugs

Prototype of direct-acting sympathomimetics:

NE and Epi are natural NT and neurohormone.

© Oxford University Press, 2013

Epinephrine (Adrenaline) as a drug

© Oxford University Press, 2013

* Because of the catechol nucleus, it is oxidized easily and

* Thus, solutions are stabilized by adding reducing

There is a chiral carbon.

At physiological pH (7.4), NE and Epi are found to exist in

© Oxford University Press, 2013

 Not taken orally

© Oxford University Press, 2013

 Presence of the β-OH and the catechol OHs and the

© Oxford University Press, 2013

© Oxford University Press, 2013

 Shows selectivity for b-adrenoceptors over α receptors

© Oxford University Press, 2013

 The receptor has a larger lipophilic binding pocket

© Oxford University Press, 2013

© Oxford University Press, 2013

•Not recognised by COMT

© Oxford University Press, 2013

© Oxford University Press, 2013

•R-Enantiomer is 68 times more active than the S-enantiomer

•Example of chiral switching

© Oxford University Press, 2013

© Oxford University Press, 2013

SAR of Direct-acting Adrenergics

SAR of Direct-acting Adrenergics

 meta-OH can be replaced with other hydrogen bonding

Aromatic ring forms van der Waals interactions

© Oxford University Press, 2013