Cardiovascular Drugs:

Beta Adrenergic Receptor Blocker

 Increased Increased Increased
sympathetic activation of β1 cardiac
activity adrenoceptors output
on heart

Decrease in Increased activation of Increased Increased

blood α1 adrenoceptors on peripheral blood
pressure smooth muscle resistance pressure

Decreased Increased Increased

renal blood renin angiotensin II
flow

Increased
aldosterone

Decreased Increased Increased

GFR Na-H2O blood
Retention volume
Beta Activation of β1 Cardiac
adrenoceptor receptors on output
blocker the heart

Renin Peripheral
resistance

 Mineralcorticoid hormone Angiotensin II

Aldosterone
Decrease in blood
pressure

Na/Water Blood
retention Volume
 Blood Pressure Regulation
also known as
Involvement of RAS
an Angiotensinogenase
system

Aldosterone is a steroid
hormone, "the main
mineralocorticoid hormone",
produced by the outer
section of the adrenal cortex
in the adrenal gland
 Diuretics
Beta
Miscellaneous
blockers

ANTI
HYPERTENSIVE
DRUGS
α2 receptor ACE
agonist Inhibitors

α1 receptor Calcium
antagonist Channel
blocker
 Antiadrenegic Drugs
According to the mechanism of action, they are divided
into:

1 Neuron Blockers
They interfere with the synthesis, storage and/or
release of the adrenergic neurotransmitter.

2 Receptor They compete for α or β-receptors.

Antagonists They have higher affinity for the receptor than
agonists, but they lack the intrinsic activity.
Effect is reversible (Competitive antagonists).
But, some receptor blockers are irreversible.
They act
by forming stable complex with receptor.
 Adrenergic Receptor Antagonists
Theory of Receptor Antagonism

• Receptor Antagonists are drugs that bind to the receptors but do not
trigger the usual receptor-mediated intracellular effects.

• i.e. they have affinity but no efficacy.

• Agonists : Affinity + intrinsic

activity
• Antagonists: only affinity
 Adrenergic Receptor Antagonists

• Drugs that bind to the adrenoreceptors but do trigger the

not usual
receptor-mediated intracellular effects.
• i.e. they have affinity but no efficacy.

• They attach to the receptor (either reversibly or thus

irreversibly), preventing its activation by the endogenous

• catecholamine.
There are two classes: - and - Blockers.

A catecholamine  (CA) is a monoamine,

an organic compound that has
a catechol (benzene with two hydroxyl side
groups) and a side-chain amine
β -Adrenoceptors
 G-Protein-coupled receptors

G protein–coupled receptors (GPCRs), also known as seven-transmembrane

domain receptors, 7TM receptors, heptahelical receptors, serpentine
receptor, and G protein–linked receptors (GPLR), constitute a
large protein family of receptors, the G-protein-coupled receptor (GPCR)
Family.

 Activate generation of cyclic AMP

Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-

cyclic adenosine monophosphate) is a second messenger important in
many biological processes. cAMP is a derivative of adenosine
triphosphate (ATP) and used for intracellular signal transduction in many
different organisms, conveying the cAMP-dependent pathway.
β -Adrenoceptors
 G-Protein-coupled receptors
 Activate generation of cyclic AMP

β1-Adrenoceptor
 Predominant receptor in heart muscle
 Activation results in cardiac muscle contraction
 Antagonists of this receptor are potential cardiovascular
drugs

β2-Adrenoceptor
 Predominant receptor in bronchial smooth muscle
 Activation results in smooth muscle relaxation

β3-Adrenoceptor
 Predominant receptor in fat cells
 Activation results in fat metabolism
Agonists and Antagonists
H OH
HO NH2
R α -agonist
HO

H OH
HO NHMe
R
α and β
HO -agonist
H OH
H
HO N

β -agonist
HO

Ar X CH2 CH2 NH R
β -antagonists
OH
Structural similarity with agonists?
Two main types of antagonists

General Ar X CH2 CH2 NH R

formula
OH

According to the Connection (X) (Spacer group)

Arylethanolamines Aryloxypropanolamines
X = Nothing X = –OCH2-- bridge
Non-selective Selective or non-selective
The prototype
A prototype drug is the first form of
a drug or medication that is used to
create alternative forms. Prototype
drugs are also called lead agents.

O N
H
OH
Propranolol
CH3

O N CH3
H
OH

(+)-1-isopropylamino-3-(1-naphthyloxy)-2-propanol

Aromatic ring: naphthalene (non-selective), and lipophilicity

Aryloxypropanolamine structure: S(+) is 100X more active than R(-).
Marketed as racemic mixture.

N-ispopropyl is a β-directing gr
Racemic mixture

In chemistry, a racemic mixture, or racemate, is one that has equal amounts of

left- and right-handed enantiomers of a chiral molecule. The first
known racemic mixture was racemic acid, which Louis Pasteur found to be
a mixture of the two enantiomeric isomers of tartaric acid. Available as HCl
salt
Propranolol

• Propanolol is the Prototype of the aryloxypropanolamine / non-

selective a β-antagonist.
• It is indicated in hypertension, angina pectoris, cardiac
arrhythmias; Myocardial Infarction;
• Control of tachycardia/ tremor associated with anxiety,
and hyperthyroidism.
• Also in migraine prophylaxis
• Contraindicated in presence of conditions such as asthma or
bronchitis
due to blockade of β2-receptors. 15
Myocardial Infarction

Myocardial infarction (MI) or acute myocardial infarction (AMI),

commonly known as a heart attack, occurs when blood flow stops to a part
of the heart causing damage to the heart muscle. The most common
symptom is chest pain or discomfort which may travel into the shoulder,
arm, back, neck, or jaw. Often it is in the center or left side of the chest and
lasts for more than a few minutes.
Synthesis

From 1-naphthol.

O
OH O

H2 O
+ Cl C C
CH2
H
-Naphthol Epichlorohydrine
CH3
CH3
H2N CH
CH3
O N CH3
H
OH

Propranolol
16
Structural Features in Propranolol
Substitution
Propanolamine group lowers
activity
Amine
Ether
O N O N
H H O N
OH H
N-
Alcohol O
OH Alkyl
H
group

Aryloxy group Naphthalene

• Naphthalene is replaceable with heteroaromatic rings

• Ether acts as a hydrogen bond acceptor
• Alcohol is essential as a hydrogen bonding group
• Amine is ionised and forms an ionic bond with the binding
site
• Amine must be secondary
• N-alkyl is a β-directing group
17
Variation of the Aryl part (naphthalene ring)

Replacing naphthalene with aryl or

heteroaryl moieties
Nadolol, Pindolol and Timolol are
aryl(heteroaryl)oxypropanolamines
They are Non selective

If the naphthalene ring is replaced by a para substituted phenyl

moiety, the resulted compounds are selective β1-blockers 18
Second generation -blockers

• Propranolol acts against both 1 and 2-adrenoceptors

• Antagonism of 2-adrenoceptors constricts airways
• Propranolol cannot be used with asthmatic patients
• Second generation -blockers are designed to be 1 –selective
• Must be para-substituted aryoxypropanolamine
• Extra hydrogen bonding interaction takes place
• Not possible with 2-adrenoceptors
• They are designed to avoid β2 antagonism (bronchospasm)

O N
H OH
H

Practolol
19
NHCOCH3
Why Para-substitution?

• must be para – substituted for 1-selectivity

• Extra hydrogen bonding interaction takes place
• Not possible with 2-adrenoceptor

O N O N
H2 H2
OH O
O H

H N
H
HN CH 3C

3
O

H H
X X

parasubstitution meta
20
Extra H-bonding interaction substitution
- Selective blockers

Aryloxypropanolamines, Aryl group is a para-substituted phenyl.

21
Aryloxypropanolamines
Remember that Aryloxypropanolamines are either selective or
non- selective

Non-selective Selective β1-

competitive antagonists
block both β1 and β2-receptors
As propranolol, nadolol, pindolol
and timolol.
(Cardio-selective)
also competitive
Block only β1 receptors
As metoprolol, atenolol, betaxolol,
bisoprolol, acebutolol, esmolol.

Selectivity of β1-antagonists is not absolute.

Caution is advised in using these agents in persons with asthma or
other
pulmonary diseases. 22
β1-Selective Blockers

 Chemical modification in compounds has

aryloxypropanolamine
resulted in β1-selective antagonists
Examples: atenolol , acebutolol, metoprolol, bisoprolol, betaxolol and
esmolol

 All β1-selecive antaginists are used for the treatment of

hypertension.
Esmolol is used for arrhythmia during surgery.
 They are designed to avoid β2 antagonism (bronchospasm)

23
 Metoprolol

1-(isopropylamino)-3-[p-(2-
methoxyethyl)phenoxy]-2-propanol

• It is indicated in hypertension; angina

pectoris; MI.
• It is available in the form of tablets
and solution for injection.
• Available as bitartrate

24
Metoprolol. Structural Features

 p-substituted phenyl: β1 selective at therapeutic doses

 Relatively lipophilic
 Changes in the p-substituent (eg. Betaxolol , Bisoprolol, Esmolol,
…. ) retain β1 selectivity.

25
 Bisoprolol

O
O

O N
H

OH

Bisoprolol Fumarate

β -Blockers with β1-receptor antagonistic

activity. Structural similarity with Metoprolol.

26
β-Blockers. SAR
Three parts
1. Aromatic ring
2. Nitrogen atom
3. Spacer

Nitrogen atom
 Amine must be secondary
 The substituent ( R ) is a β-directing group: Isopropyl, t-butyl,
aralkyl
 Branched N-alkyl group fits a hydrophobic pocket
 Extension of N-alkyl group with N-arylethyl group is beneficial
 Amine is ionised and forms an ionic bond with the binding site

27
β-Blockers. SAR
Ar X CH CH2 NH R
The spacer:
OH

Either Two carbon atoms ( gives aryl-ethanolamines)

Or OCH2 + 2 carbons ( gives aryl-oxypropanolamines)

28
β-Blockers. SAR

The spacer: Ar X CH CH2 R

NH
*
OH

Alcohol is essential as a hydrogen bonding group

Carbinol carbon is asymmetric: (Stereo-chemistry depends on X)

– Arylethanolamines: R is most active
– Aryloxypropanolamines: S is most active

29
β-Blockers. SAR
The spacer

Arylethanolamine R
Aryloxypropanolamine
S
Groups are in the same
relative position, but
substituents change
absolute b c
CH2 NHR CH2 NHR
configuration.
a C c a C b
HO HO
CH2 O
H H

30
β-Blockers. SAR
Ar X CH CH2 NH R
The spacer *
OH

in case of Arylethanolamines ( X = nothing )

 All compounds in this class are non-
selective

In case of Aryloxypropanolamines (X = -OCH2- )

 Ether acts as a hydrogen bond acceptor

31
β-Blockers. SAR Ar X CH CH2 NH R
*
OH
Aryl nucleus (Ar): in
aryloxypropanolamines
• Naphthyl gr of propranolol: non-selectibe
• Substituted naphthyl: also Non-selective
• Naphthalene of propranolol is replaceable with heteroaromatic
• rings Heteroaromatic rings: non-selective; e.g. Pindolol and Timolol
• If phenyl:
• Non-substituted phenyl : non-selective β-
• antagonism Substituted phenyl:
– Chemical nature affects potency but not
selectivity
–
Para substituted results in β1 selectivity
–
Small ortho-substituents retain β1
–
selectivity 32
Summary

33