Adrenergic Drugs

• Agents that act on peripheral sites of the sympathetic NS

• Act via
- Enhancing the sympathetic activity (sympathomimetics,
adrenomimetics, or adrenergic stimulants) or
- Inhibiting the sympathetic activity (sympatholytics, anti-
adrenergics or adrenergic blocking agents.

• Norepinepherine (NE) and Epinepherine are the main adrenergic

neurotransmitters.

• Norepinephrine and Epinepherine belong to catecholamine group of

structures
Norepinephrine and Epinephrine
NE is synthesized and liberated from postganglionic symp. Neurons on -
.stimulation
It interacts with specific presynaptic receptors (α2) and postsynaptic *
.receptors (α1, β1 and β2)
:It is terminated by•
Reuptake -1•
.Metabolism ( MAO and COMT are the effective enzymes)-2 •
:Epi. is synthesized in adrenal medulla and Released into circulation -
Interact with adrenergic receptors same way as NE *
Terminated by metabolism ( MAO and COMT are the effective *
.enzymes)
 Biosynthesis of Norepinephrine

(Phenylethanolamine N-methyltransferase)
Norepinephrine Epinephrine
 Neurotransmission Events in an
Adrenergic Neuron and Effectors

Synapse
 Metabolism of Norepinephrine

1 2

1= 3-methoxy-4-Hydroxymandelic acid – urine

2=3’-Methoxy-4’-OH phenylglycol - CNS
 View from the extracellular side
View from the extracellularHelix
side
Serine 204

Serine 207

Binding Site

Aspartate 113
Norepinephrine, hypothesis for its binding
with receptor site

Extended conformation
Norepinephrine, hypothesis for its binding
with receptor site
Adrenergic Drugs

• Direct-acting agonists bind to and activate

alpha1, alpha2, beta1 and beta2 receptors
• Indirect-acting adrenergic agonists produce NE-
like actions by stimulating NE release and
preventing its re-uptake and thus its inactivation
• Dual-acting adrenergic agonists act as a direct-
and an indirect-adrenergic agonists - they bind
to adrenergic receptors and stimulate NE
release.
Tissue Responses to Stimulation of
Adrenoceptor Subtypes
Structure Activity Relationships
(SAR) of Adrenergic Drugs
• Drugs that act directly on the receptors as
agonists and antagonists
• Drugs that affect storage and release of
norepinephrine from vesicles
• Drugs that affect norepinephrine biosynthesis
• Drugs that affect uptake and catabolism of
norepinephrine and epinephrine.
Members of Direct-Acting Sympathomimetics
Phenylethanolamine Adrenergic Agonists

OH
2' NH R
1
3' 1 2
R3 R2
4' 6'
5'
 Chemistry of Epinephrine and
Norepinephrine

OH
Phenolic hydroxyl grougs, Acidic Amine Physiologic pH
Secondary alcoholic function 7.4 OH NH3
group
OH H

HO NH2 OH

Catechol moiety H
Cation
HO
Alkyl side chain 95%
OH Interact with the receptors
(R)(-) Norepinephrine
HO NHCH3

HO

(R)(-) epinephrine
 Norepinephrine
OH

HO NH2

HO

(R) (-) 4-(2-Amino-1-hydroxy-ethyl)-benzene-1,2-diol

Newman projection formula

Extended conformation
 Members of Direct-Acting Sympathomimetics,
Epinephrine
OH

HO NHCH3

HO

-The levorotatory isomer [(R) (-)] enantoimer is more active than Dxtro
[(S) (+)]
-Because of the catechol nucleus, it is oxidized easily and darken
slowly on exposure to air, thus solutions are stabilized by reducing
agents as sodium bisulfite or ascorbic acid
- Because of the two phenolic groups it has an irritating action
(stinging action)
- It is a very good precursor for MAO and COMT, so it could not be
administered orally and has a very short duration of action
Members of Direct-Acting Sympathomimetics,
Derivatives of Epinephrine

• To overcome the singing action of catechol

moiety, a complex between epinephrine and
boric acid that may have the following structure
is made and used as sodium salt as ophthalmic
solution
OH

O NHCH3

Na O B

Sodium Epinephryl Borate

 Members of Direct-Acting Sympathomimetics,
Derivatives of Epinephrine and norepinephrine

•
O OH
To achieve much better effect
• To reduce Toxicity
(H3C) 3C C O NHCH3

• To reduce irritability
• To increase the duration of (H3C) 3C C O
Dipivefrin
action, O

Epinephrine is converted to
diester derivative, Known as Estrases
Dipiverfin (Prodrug, inactive)
- Dipiverfin is the pivalic acid
ester, which is more lipophilic
OH

than the parent HO NHCH3

- In cornea, it is converted to 2(CH3)C COOH

epinephrine (active) HO

Epinepherine Pivalic acid

 Members of Direct-Acting Sympathomimetics,
Derivatives of Epinephrine and norepinephrine

• 4- Deoxyepinephrine (c.f., phenylephrine) is a

direct α1-receptor agonist and is twice active than
epinephrine, i.e., Removal of 4-OH group increases
selectivity and reactivity toward α1-subreceptor
• N.B. 4-OH is important for β-action
OH

HO NHCH3

.HCl

Phenylephrine Hydrochloride
 Members of Direct-Acting Sympathomimetics, Derivatives
of Epinephrine and norepinephrine

N-Alkyl substituent has a role to play in receptor selectivity

Increasing the size of the N-alkyl substituent resulted in loss
of potency at the α-receptor but an increase in potency at
β-receptors e.g., Isoprenaline (isoproterenol) is a
powerful β-stimulant (still non selective for β-receptors
subtypes, act on both β1 and β2),which means that the β-
receptor has a hydrophobic area which a bulky alkyl group
can fit. Adrenoreceptors does not have.
OH

H
HO N CH3

Isopropyl substituent
CH3
HO

Isopretrenol (isoprenaline)
 Hypothetical Illustration of Binding of
Norepinephrine and Isoproterenol to α- and β-
receptors, respectively.

β-Receptor α-Receptor
 How can the β2-Agonist Selectivity of
Isoproterenol be improve?
• Substitution of Isopropylmoiety by tert-butyl,e.g. Colterol
• Used as a prodrug (diester) known as Bitolterol
• The presnce of the two tolyl moieties makes it more
lipophilic, Which means increased duration of action
O OH
COOH
OH
H3C O NHC(CH3)3
HO NHC(CH3)3

Esterase 2
H3C O
HO
O
CH3
Colterol
Pro-drug (Bitolterol) p-Toluic Acid
 How can the β2-Agonist Selectivity of
Isoproterenol Improved?

• Replacement of OH
CH3

catechol moiety by HO NHCH

CH3

resorcinol.
• Resorcinol derivatives OH

are not substrates of Metaproterenol

COMT. OH
CH3

• Examples are
HO NHC
CH3
CH3

- Metaproterenol
- Terbutaline OH

Terbutaline
 How can the β2-Agonist Selectivity of
Isoproterenol Improved?
• Replacement of 3-OH group by CH2OH group as in
Albuterol; Salbutamol (Ventoline)
• Albuterol is not a substrate for COMT
• Albuterol has longer duration of action than colterol
• Used to treat bronchial spasm associated with asthma.

OH
CH3

HOH2C NHC
CH3
CH3

HO

Albuterol
 How can the β2-Agonist Selectivity of
Isoproterenol Improved?
• Increased lipophilicity was introduced by using a long hydrocarbon
chain as one of N-substituents
• Example is
- Salmeterol
- logP=3.3 =12 hours duration of action,
- while Albuterol: logP= 0.66 = 4 hours duration.

OH
H
N
HO O

HO
Salmeterol
 OH

H
N
HO O

HO

Salmeterol
Salmetrol

OH

OH
N
H2

HO

Specific binding of phenyl group at the end of the extended side chain with
a specific region of the  2 receptor

Salmeterol (log P =3.3, duration of action is 12 hours) is a modified form of albuterol

(log P =0.66, duration of action is 4 hours). The extended duration of action of
salmeterol is due to the specific binding (anchoring) of the phenyl group at the end of
the extended lipophilic side chain with a specific region of the β2 –receptor, affording
salmeterol a unique binding mechanism.
 How can the β2-Agonist Selectivity of
Isoproterenol Improved?

• Insertion of C2H5- at α-carbon Example is

isoetharine.

OH

HO NHCH(CH3)2

C2H5
HO

Isoetharine
Phenylethanolamine Adrenergic Agonists:
Summary
Other Selective β2-Agonist: Ritoderine

• 3-Dehydroxylation
• α-Substitution by Alkyl group increases Beta over Alpha
• N-substitution by a long hydrocarbon chain to increase lipophilicity
• These modifications in norepinepherine structure led to Ritodrine
that has a long duration of action and β2-selectivity.
• Ritodrine is selective on β2 –receptors of the uterus, thus results in
relaxation of uterine muscles and used to prevent premature labor.

OH

H
N


CH3
HO OH

Ritodrine
β1-Adrenergic agonists
• Dopamine HO

HO NH2
dopamine

Dopamine acts on specific dopamine receptors to dilate renal vessels, increasing renal blood flow. It
stimulates cardiac β1-receptors through direct and indirect mechanisms. It is used to correct
hemodynamic imbalances induced by conditions such as shock, myocardial infarction, trauma or
congestive heart failure. It is metabolized by COMT and MAO and not used orally.

HO
• Dobutamine CH3

HO N
H

Dobutamine OH
 Phenylethanolamine Adrenergic Agonists: R2 Substitution

Mixed function Adrenergic Agonist

• Substitution on α-carbon introduces another asymmetric

center producing a pair of diastereomers with different
biological and chemical properties: Maximal activity resides in
1R,2S (erythro) stereoisomer.
• Example are ephedrine and pseudoephedrine.
• N.B. Both do not have any substituent on phenyl ring, it is
not a substrate for COMT, and could be taken orally.
• Pseudoephedrine is preferred orally as nasal decongestant
because it has less central stimulating properties compared
to ephedrine.
Ephedrine and Pseudoephedrine
CH3
CH3

H NHCH3
2S H3CHN
2R
H

H OH
1R HO H
1S Enantiomers

Erythro
Enantiomers

Ephedrine
CH3 CH3

2R 2S
H3CHN H H NHCH3
1R
Threo 1S
H OH HO H
Enantiomers

Pseudoephedrine
Indirect Acting Sympathomimetics
Indirect Acting, Sympathomimetics (no action on receptors, taken up into
the presynaptic neuron, cause the release of NE):

. Amphetamine

NH2

CH3
Other amphetamine derivatives
NHCH3

Methamphetamine, Methylamphetamine, alpha substitution

by methyl delays the action of MAO

NHCH3

Propylhexedrine, Replacing phenyl portion by cyclohexyl increases

lipophilicity

NHCH3

Mephentramine, Because of the presence of two methyl groups

on alpha carbon, the compound is not a good substrate for MAO
Imidazoline Agonists: Alpha-1 Agonists:
H
N
N

N N
H

Naphazoline
Tetrahydrozoline

H
H N
HO N

N
N

Oxymetazoline
Xylometazoline
Imidazoline Alpha-2 Agonists
Cl

H H
N N

N
Cl

Clonidine

Non-imidazoline Alpha-2 agonists

Cl
Cl
H
N H
NH2 N
N NH2

HN O
Cl HN
Cl

Guanabenz Guanfacine
Adrenergic Antagonists
- Alpha Adrenergic Blockers:
- Reversible Blockers
. Imidazoline drugs:
Tolazoline,
Phentolamine

CH3
Phentolamine

H
N
N
N

HO
Phenoxybenzamine; Interaction With α-
Receptors (Irreversible blocker)
Selective Alpha-1 Antagonists
• Quinazoline derivatives: 4-amino-6,7-dimethoxy-quinazoline
ring system attached to a piperazine ring system

piperazine
 Why tetrahydrofuran is more hydrophilic
than furan?

O
O

lone pair is involved in lone pair is available on the oxygen

conjugation with the ring and can form hydrogen bonding and
dipole- interaction with water molecules
CLogP: 1.318
CLogP: 0.526
 Uroselective α1-Blockers

• Tamsulosin and Afluzosin are

two recent selective α-blockers
acting specifically on
subreceptors- α1A that present
in prostate (Uroselective α1A
blockers). They are useful Tamsulosin
drugs for reducing symptoms
of benign prostatic hyperplasia O CH3

(BPH) and are generally H

N N N O

associated with less severe

side effects compared to the O N
O
other selective α-blockers. Afluzosin
NH2
Beta-Adrenergic Blockers (Beta Antagonists)
, First Generation
• The most useful adrenergic antagonist used in
medicine today are the β-Blockers specially β1-
antagonist.
• The first goal in the development of these agents
was to achieve selectivity for β-receptors with
respect to α-receptors.
• Isoprenaline was chosen as the lead compound.
• Isoprenaline is a β-agonist and not antagonist
• So the goal is to modify the molecule to convert it
from an agonist to an antagonist.
 How can this be achieved?
•
OH
The phenolic groups are important for H
agonist activity. HO
H
N

• This does not necessarily mean that Beta agonist

they are essential for antagonist
activity HO Isoprenaline

• Replacement of these phenolic OHs of

isoprenaline by chlorine atoms givining OH
rise dichloroisoprenaline (DCl), which H
H
act as partial agonist Cl N

• The common tactic used in medicinal Partial agonist

chemistry when trying to convert an Cl
agonist into antagonist is to add an
extra aromatic ring Dichloroisoprenaline

• This can sometimes result in an extra OH

hydrophobic interaction with the H
receptor which is not involved when H
N

the agonist binds, therefore the two Still partial agonist

chlorine atoms are replaced by
benzene ring The first drug
used for angina,
Pronethalol arrythmias and
high blood pressure
What Effect Would Be There In Extending
The Length Of The Chain Connecting The
Aromatic Ring With The Amine?

It was Intended to synthesize the following target structure

starting from β-naphthol

Linking Group

HO
X
N
H
H

Aromatic Portion Amine Portion

 What a good fortune………???
• β-Naphthol was not in stock at
this time and so synthesis was
carried out using α- naphthol
• This led to propranolol, which was H

found to be pure antagonist, and O N

H
which was 10-20 times more OH

active than pronethalol, the S-

enantiomer is the active
enantiomer*
Propranolol;
* Although the S-enantiomer of aryloxyalkylamunes and the R- Non-selective
enatiomer of arylethanolamilnese the active forms, the orientation
of groups about the two assymmetric centers is the same for both
classes.
Propranolol; SAR
 Structure activity relationship (SAR) of aryloxypropanolamines
There are general requirements in this class for β-blocking activity. Numerous studies have
identified the SAR of this type of compounds.

General structure

γ β α
Ar
O NHR
OH

1. Side chain
Substitution on the α, β or γ carbon atoms decreased the β-blocking activity,
however methylation of α-carbon atom generally produced β2-selective blocker than β1.
Extension of oxypropanolamine side chain by one carbon as well as
replacement of ethereal oxygen by methylene group, sulfur atom or nitrogen atom
virtually eliminated activity.
Complete removal of ethereal oxygen considerable lowered the β-blocking
activity.
β-Hydroxyl group is important for β-blocking activity. Removal or substitution
caused a marked reduction in activity. For maximum effectiveness in receptor
binding, the hydroxyl group must occupy the same region in space as it does in
the arylethanolamine and natural agonist epinephrine and norepinephrine in
the R absolute configuration.
Because of the insertion of an oxygen atom in the side chain of
aryloxypropanolamine, the Cahn-Ingold-Prelog priority of the substituents
around the asymmetric carbon changes, and the isomer with the required
special arrangement now has the S absolute configuration. However, the
groups still have the same spatial arrangements.
Other Non-Selective β-Blockers
O N O N
H H

OH OH

O N
H
Propranolol Carteolol

O N
H O N
H
OH
HO OH

HO

O
Levobunolol
Nadolol

O N
O N H
H
OH
OH

N
H
Pindolol Penbutolol

O N O N
H H
O
OH H3 C OH
N
N

N S
H3 C CH 3
Timolol Metipranolol
OCOCH 3

OH

H
N
CH 3
O
S
N
O H
Sotalol

Nonselective beta-blockers
 Selective β1-blockers; Second Generation

• Propranolol is non-selective
• It does pose a problems if patient is
asthmatic H

• Because of its hydrophobic characters, O N

H
it has CNS action, it lowers the overall OH

sympathetic activity
• So design of β1-selective blockers was
very important. NHCOCH3

• Practolol is not as potent as Practolol

propranolol, but lakes all problems of
propranolol
• It was more polar has low CNS effect
• Introduction of p-acetamido group
means extra H-bonging interaction
with the receptor
 Selective β1-blockers; Second Generation

• Replacement of
acetamido group with
other groups capable
of hydrogen bonding
led to a series of
cardio-selective β1-
blockers.
O N O O N
H H O N
H
OH OH
OH
H3C

Atenolol
Acebutolol Betaxolol

CH2CONH2 NHCOCH2CH2CH3
CH2CH2OCH2

O N
H O N
H
OH O N
OH H

OH
Bisoprolol Metoprolol
Esmolol
CH2OCH2CH2OCH(CH3)2 O
CH2CH2OCH3

Selective beta1-blockers

O N
H O N
H2
OH Serum Esterases OH

Esmolol
O Half-time 8 minutes
O Zwitter ion
O
O
Mixed α/ β-adrenergic Antagonists
OH

H
N

CH 3

• Labetalol and Carvidolol HO

Labetalol

• Labetalol (α1β1β2 antagonist and Partial O NH2

agonist at β2 receptors, β : α is 4-7:1) &

carvidolol (β : α is 10:1) have an unusual
OCH3

activity in that they are antihypertensive

O
O N
H

with α1­, β1 -, and β2 – blocking activity. OH

Although large group such isopropyl and

tert-butyl eliminate α-receptor activity, yet N
H
Carvidolol

still larger groups could bring back α 1-

affinity but not intrinsic activity. Thus ,
these drugs labetalol and carvidolol have
structural features permitting binding to Beta-blockers with alpha 1-receptor antagonist ativity

both the α1-blocking activity and non-

selectively to both β-receptors. Thus, these
drugs are used to control hypertension via
α1-blocking activity and prevent the OH H
resulting reflex tachycardia produced from O N
vasodilatation by the β –blocking activity.
OCH3
• Bevantolol is a selective beta1 antagonist OCH3
with unique partial agonist action on alpha
receptors

Bevantolol
 Selective β1-blockers; Third Generation

• Replacement of
N-isopropyl
with aralkyl
groups resulted
in a series of
third generation
of selective β1-
blockers
Biosynthesis of Norepinephrine

(Phenylethanolamine N-methyltransferase)
Norepi Epinephrine
 Drugs Affecting Nor/Epinephrine
Biosynthesis
• Inhibitors of tyrosine hydroxylase: e.g. alpha-methyl-L-
tryrosine (Metyrosine)
• Inhibitors of aromatic L-amino acid decarboxylase: e.g.
Carbidopa
HO
S CH3 CH3
HO COOH HO COOH
NH2 NHNH2

Metyrosine Carbidopa
Alpha-methyltyrosine
HO
H2N
COOH

HO
H
Levodopa
 Drugs Affecting Storage Vesicles, Prevent
the release of NE

• Reserpine CH3O N
H H
N
H

• Bretylium tosylate
OCH3
Reserpine H
CH3OOC OOC OCH3

• Guanethidine & OCH3

OCH3

Guanadrel
Dioxaspirodecyl ring NH2

O HN

SO3
NH Br
O
CH3
Hexahydroazocinyl
Ethyl guanidine N
Guanadrel CH3

H C2H5
N N
NH2

CH3
HN
Bretylium Tosylate

Guanithidine
 End of
Adrenergic
Agents
(October. 2007)