ADRENERGIC AGENTS 1

Assistant Prof Dr. Dana Ameen, HMU -College of Pharmacy, 12th Sep. 2023
 Catecholamines
• The name catecholamine was given to these
compounds because they contain an amino group
attached to an aromatic ring that contains two
hydroxyl groups situated ortho to each other, the
same arrangement of hydroxyl groups as found in
catechol.
H OH
HO NHR HO

HO HO

(R)-Epinephrine; R= CH3 Catechol

(R)-Norepinephrine; R= H
 ENDOGENOUS CATECHOLAMINES
• The three naturally occurring catecholamines
dopamine, norepinephrine (NE), and epinephrine
are used as therapeutic agents.

H OH
HO NHR HO NH2

HO HO

(R)-Epinephrine; R= CH3 Dopamine

(R)-Norepinephrine; R= H
 Catecholamines Biosynthesis
NH2 HO NH2 L-Aromatic Amino Acid
Tyrosine Hydroxylase Decarboxylase
COOH COOH
HO HO
Tyrosine L-Dihydroxyphenylalanine

OH
HO NH2 Phenylethanolamine
HO NH2 N-Methyltransferase
Dopamine B-Hydroxylase
HO HO
Dopamine NE

OH
H
HO N
CH3

HO
Epinephrine
 Stability of catecholamines
• Catecholamines undergo oxidation in the presence
of oxygen (air) or other oxidizing agents to produce
ortho-quinone-like compounds, which undergo
further reactions to give mixtures of colored
products. Hence, solutions of catecholamine drugs
often are stabilized by the addition of an
antioxidant (reducing agent) such as ascorbic acid
or sodium bisulfite.
H OH H OH
HO NHR O NHR
oxygen (air)
HO oxidants O
(R)-Epinephrine; R= CH3 ortho-Quinone
(R)-Norepinephrine; R= H inactive
 Dopamine
• Dopamine is used in the treatment of shock.
• It is used intravenously as it is ineffective orally, in
large part because it is a substrate for both MAO
and COMT.
HO NH2

HO

Dopamine
 Norepinephrine (NE)
• Like the other endogenous catecholamines, it is a
substrate for both MAO and COMT and thus is not
effective by the oral route of administration.
• The enantiomer with the (R) configuration is
biosynthesized in the body and possesses the
biological activity.
H OH
HO NHR

HO
(R)-Epinephrine; R= CH3
(R)-Norepinephrine; R= H
 Epinephrine
• Like the other catecholamines, epinephrine
is light sensitive and easily oxidized on
exposure to air because of the catechol ring
system.
• The development of a pink to brown color
indicates oxidative breakdown.
H OH
HO NHR

HO
(R)-Epinephrine; R= CH3
(R)-Norepinephrine; R= H
 Epinephrine
• To minimize oxidation, solutions of the drug are
stabilized by the addition of reducing agents such
as sodium bisulfite. As the free amine, it is used in
aqueous solution for inhalation.
• Like other amines, it forms salts with acids; for
example, those now used include the hydrochloride
and the bitartrate.
 Epinephrine
• It is destroyed readily in alkaline solutions and by
metals (Cu, Fe, Zn), weak oxidizing agents, and
oxygen of the air.
• It is not effective by the oral route because of poor
absorption and rapid metabolism by MAO and
COMT.
• The irritation often experienced on instillation of
epinephrine into the eye has led to its
development of other preparations of the drug
that potentially are not as irritating. One such
example is dipivefrin.
 Dipivefrin (dipivalyl epinephrine)
• Dipivefrin is a prodrug of epinephrine that is
formed by the esterification of the catechol
hydroxyl groups of epinephrine with pivalic acid.
• Dipivefrin is much more lipophilic than
epinephrine and it achieves much better
penetration of the eye when administered
topically as an aqueous solution for the treatment
of primary open-angle glaucoma.
• Dipivefrin is converted to epinephrine by esterases in the
cornea and anterior chamber.
• It offers the advantage of being less irritating to the eye than
epinephrine and because of its more efficient transport into
the eye, it can be used in lower concentration than
epinephrine.

O OH
OH
O NHCH3 HO NHCH3
Esterases O
+ 2
O HO OH

O Dipivefrin Epinephrine
 The active enantiomer
• Epinephrine and NE each possess a chiral carbon
atom; thus, each can exist as an enantiomeric pair
of isomers. The enantiomer with the (R)
configuration is biosynthesized in the body and
possesses the biological activity.
H OH H OH
HO NHR HO NHR

HO HO
(R)-Epinephrine; R= CH3 (S)-Epinephrine; R= CH3
(R)-Norepinephrine; R= H (S)-Norepinephrine; R= H
 Catecholamines are hydrophilic
• As they are polar substances that contain acidic
(the aromatic hydroxyls pKa 8.7) and basic (the
aliphatic amine pKa 9.9).
 Metabolism of catecholamine
OH OH OH
HO HO NHR 1- MAO HO COOH
CHO MAO
2- Aldehyde
HO HO Dehydrogenase HO
3,4-Dihydroxyphenyl- Epinephrine; R= CH3 3,4-Dihydroxymandelic acid
glycolaldehyde Norepinephrine; R= H

Aldehyde COMT
Reductase

OH OH
HO H3CO NHR
CH2OH
COMT
HO HO
3,4-Dihydroxyphenyl- Normetanephrine; R= CH3
ethylene Glycol
Metanenephrine; R= H
1-MAO 1-MAO
COMT 2-Aldehyde 2-Aldehyde
Reductase Dehydrogenase

OH OH
H3CO H3CO
CH2OH 1-Alcohol Dehydrogenase COOH
2-AldehydeDehydrogenase
HO HO
3-Methoxy-4-hydroxy- 3-methoxy-4-hydroxy-
phenylethylene Glycol mandelic acid
 α- and β-Adrenergic Receptors
• The α1 and α2 receptors each have been divided
into at least three subtypes: αlA, α1B, α1D and α2A,
α2B, α2C, respectively.
• The β1-receptors exhibit the agonist potency order
isoproterenol > epinephrine = NE
• While β2-receptors exhibit the agonist potency
order isoproterenol > epinephrine >> NE.
• The β3-receptor, the agonist potency order is
isoproterenol = NE > epinephrine.
 Drugs Affecting Catecholamine Biosynthesis
• Metyrosine (α-methyl-p-tyrosine) is inhibiting
tyrosine hydroxylase.
• It is the (—) isomer that possesses the inhibitory
activity but the racemic mixture is used.
• Metyrosine is used orally for the preoperative
management of pheochromocytoma.
• Mainly excreted unchanged in the urine and
because of its limited water solubility, crystalurea
is a potential serious side effect. NH2
COOH
H3C
HO
Metyrosine
 Drugs Affecting Catecholamine Storage
• Reserpine, deserpidine and rescinnamine
Reserpine is an indole alkaloid obtained from the
root of Rauwolfia serpentina, a climbing shrub
found in India.
• Reserpine binds with the ATP-driven monoamine
transporter that transports NE and other biogenic
amines from the cytoplasm into the storage
vesicle.
• Both the pure alkaloid and the powdered whole
root of R. serpentina are used in the treatment of
hypertension.
• Reserpine is extensively metabolized through
hydrolysis of the ester function at position 18.
This yields methyl reserpate and 3,4,5-
trimethoxybenzoic acid.
• As is typical of many indole alkaloids, reserpine is
susceptible to decomposition by light and
oxidation.
H O
N R2 OCH3
O
R1 N H Rescinnammne: R1 = OCH3, R2=
H OCH3
H
H3CO2C OCH3
OCH3

OCH3 OCH3

Deserpidine: R1 = H, R2= OCH3 Reserpine: R1 = OCH3, R2= OCH3

OCH3 OCH3
 Drugs Affecting Catecholamine Release
• Guanethidine and Guanadrel prevent the release of NE from
sympathetic nerve terminals and are used clinically in the treatment
of hypertension.

• The presence of the very basic guanidino group (pKa> 12) means
that at physiological pH they are essentially completely protonated.
Thus, these agents do not get into the CNS.
 Guanethidine Guanadrel

Bioavailability 3-50% 85%

Half-life 5 days 12 hours

• Both agents are partially metabolized (~50%) by

the liver, and both are used to treat moderate-to-
severe hypertension.
 Bretylium Tosylate
• It is an aromatic quaternary ammonium
compound used as an antiarrhythmic drug.

• Its antiarrhythmic actions are not due to its

neuronal blocking effects.
 SYMPATHOMIMETIC AGENTS
• Direct-acting agents elicit a sympathomimetic
response by interacting directly with adrenergic
receptors.
• Indirect-acting agents produce effects primarily by
causing the release of NE from adrenergic nerve
terminals: the NE that is released by the indirect-
acting agent activates the receptors to produce the
response.
• Mixed-acting agents interact directly with
adrenergic receptors and cause the release of NE.
 Direct-Acting Sympathomimetics
STRUCTURE-ACTIVITY RELATIONSHIPS
• Maximal activity is seen in β-phenylethylamine
derivatives containing hydroxyl groups in the meta
and para positions of the aromatic ring (a
catechol) and a β-hydroxyl group of the correct
stereochemical configuration on the ethylamine
portion of the molecule. Such as NE, epinephrine,
and isoproterenol.

meta
NH2

para 
Easson-Stedman hypothesis
interaction of three critical
pharmacophoric groups of (-)-(R)-NE
with the complementary areas on
the adrenergic receptor.
 The amino group
• The amino group should be separated from the
aromatic ring by two carbon atoms for optimal
activity.
• Primary and secondary amines are potent direct-
acting agonists.
• Tertiary or quaternary amines are poor direct
agonists. 
meta
NH2 1o and 2o
para 
 The amino group
• As the bulk of the nitrogen substituent increases,
α-receptor agonist decreases and β-receptor
activity increases.
• Example: Isoproterenol has little affinity for α-receptors
but it is a potent β1 and β2-receptor agonist.

meta
NH2

para 
• The nature of the substituent can also affect β1/β2-receptor
selectivity.

• Example, N-tert-butyl norepinephrine is 10 times as potent

an agonist at tracheal β2-receptors than at cardiac β1-
receptors.
• Large substituents on the amino group also protect the amino group
from undergoing oxidative deamination by MAO.
 Substitution on the α-carbon
• Alkyl substitution on the α-carbon reduces direct
receptor agonist activity at both α- and β-
receptors.
• But an α-alkyl group increases the duration of
action of the phenylethylamine agonist by making
the compound resistant to metabolic deamination
by MAO. Such compounds often exhibit enhanced
oral effectiveness and greater CNS activity than
their counterparts that do not contain an α-alkyl

group. meta
NH2

para 
 Substitution on the α-carbon
• α-Methyl substitution gives compounds with
selectivity toward the α2-recepor.
• α-Ethyl substitution results in compounds with
selectivity toward the β2-receptor
• Another effect of α-substitution is the introduction
of a chiral center. Example, with α-
methylnorepinephrine, it is (1R,2S)-isomer that
possesses significant activity at α-receptors.
 Replacement of the catechol moiety
• Replacement of the catechol function of
isoproterenol with the resorcinol structure gives
the drug metaproterenol, which is a selective β2-
agonist. The resorcinol ring is not a substrate for
COMT, has better absorption characteristics and a
longer duration of action.
 Replacement of the catechol moiety
• Replacement of the meta-hydroxyl of the catechol
structure with a hydroxymethyl group gives agents, such
as albuterol, which show selectivity to the β2-receptor.

• As in the case of the resorcinol modification, they are not

metabolized by COMT and thus show improved oral
bioavailability.
 Replacement of the catechol moiety
• Removal of the p-hydroxyl group from epinephrine
gives phenylephrine, which, in contrast to
epinephrine, is selective for the α1-adrenergic
receptor. OH
HO NHCH3

Phenylephrine
 Imidazoline α-adrenergic receptor agonists
• These imidazolines can be nonselective, or they
can be selective for either the α1- or α2-adrenergic
receptors. Structurally, imidazolines for the most
part have the heterocyclic imidazoline nucleus
linked to a substituted aromatic moiety via some
type of bridging unit.
Aromatic
moiety Ar N
X Imidazoline
N ring
Bridging H
unit
 Imidazoline α-adrenergic receptor agonists
• Modification of the imidazoline ring generally
results in compounds with significantly reduced
agonist activity, there are examples of so-called
open-ring imidazolines (guanabenz and
guanfacine) that are highly active.

Aromatic
moiety Ar N
X Imidazoline
N ring
Bridging H
unit
 Imidazoline α-adrenergic receptor agonists
• The optimum bridging unit (X) is usually a single
amino or methylene group.
Aromatic
moiety Ar N
X Imidazoline
N ring
Bridging H
unit
H3C H3C
N
CH3 CH3
R
N CH3 CH3
H R= CH3 CH3
H3C OH H3C

Naphazoline Tetrahydrozoline Oxymetazoline Zylometazoline

 Imidazolidine α-adrenergic receptor agonists
• The nature of the aromatic moiety, as well as how
it is substituted, is quite flexible.
• However, agonist activity is enhanced when the
aromatic ring is substituted with halogen
substituents like Cl or small alkyl groups like
methyl, particularly when they are placed in the
two ortho-positions.
H Cl
N Clonidine: R= H
N R 4-Hydroxyclonidine: R= OH
N
H Apraclonidine: R= NH2
Cl
 α-ADRENERGIC RECEPTOR AGONISTS
• Phenylephrine is the prototypical selective direct-
acting α1-receptor agonist.
• It is active when given orally, and its duration of
action is about twice that of epinephrine.
• It is metabolized by MAO, but since it lacks the
catechol moiety, it is not metabolized by COMT.
OH
HO NHCH3

Phenylephrine
 Methoxamine
• It is selective direct-acting α1-receptor agonist used
therapeutically.
• It is less potent than phenylephrine as a
vasoconstrictor. Methoxamine is used primarily
during surgery to maintain adequate arterial blood
pressure, especially in conjunction with spinal
anesthesia. It does not stimulate the CNS.
CH3O OH
NH2
Methoxamine
CH3

OCH3
 Midodrine
• Midodrine represents another example of a
dimethoxy-β-phenylethylamine derivative that is
used therapeutically for its vasoconstrictor
properties.
• Midodrine is the N-glycyl prodrug of the selective
α1-receptor agonist desglymidodrine. Removal of
the N-glycyl moiety from midodrine occurs readily
in the liver as well as throughout the body,
presumably by amidases. CH3O OH
NHCOCH2NH2

Midodrine
OCH3
 Naphazoline, Tetrahydrozoline,
Xylometazoline, and Oxymetazoline
• The 2-aralkylimidazolines are agonists at both α1
and α2-adrenergic receptors. These agents are
used for their vasoconstrictive effects as nasal and
ophthalmic decongestants.
H3C H3C
N
CH3 CH3
R
N CH3 CH3
H R= CH3 CH3
H3C OH H3C

Naphazoline Tetrahydrozoline Oxymetazoline Zylometazoline

 Naphazoline, Tetrahydrozoline,
Xylometazoline, and Oxymetazoline
• They have limited access to the CNS, since they
essentially exist in an ionized at physiological pH
because of the very basic nature of the imidazoline
ring (pKa 9 to 10).
H3C H3C
N
CH3 CH3
R
N CH3 CH3
H R= CH3 CH3
H3C OH H3C

Naphazoline Tetrahydrozoline Oxymetazoline Zylometazoline

 Clonidine
• It is an example of α-(phenylimino)imidazolidine
derivative that possesses selectivity for the α2-
adrenergic receptor.
• The ability of clonidine and its analogues to exert
an antihypertensive effect depends on the ability
of these compounds not only to interact with the
α2-receptor but also to gain entry into the CNS.

H Cl
N Clonidine: R= H
N R 4-Hydroxyclonidine: R= OH
N
H Apraclonidine: R= NH2
Cl
 SAR of clonidine and its analogues
• In the case of clonidine, the basicity of the guanidine group

(typically pKa 13.6) is decreased to 8.0 (the pKa of clonidine) because

of its direct attachment to the dichlorophenyl ring. Thus, at

physiological pH, clonidine will exist to a significant extent in the

nonionized form required for passage into the CNS.

H Cl
N Clonidine: R= H
N R 4-Hydroxyclonidine: R= OH
N
H Apraclonidine: R= NH2
Cl
 SAR of clonidine and its analogues
• Substitutions on the aromatic ring with various
halogen and alkyl can be placed at the two ortho
positions without affecting the affinity of the
derivatives toward α2-receptors, such
substitutions have a marked effect on the
lipophilicity of the compound to gain entry into
the CNS to produce an antihypertensive effect.

H Cl
N Clonidine: R= H
N R 4-Hydroxyclonidine: R= OH
N
H Apraclonidine: R= NH2
Cl
 SAR of clonidine and its analogues
• Halogen substituents such as chlorine seem to
provide the optimal characteristics in this regard.
This distributive phenomenon is seen with one of
the metabolites of clonidine, 4-hydroxyclonidine.
This compound has good affinity for α2-receptors,
but since it is too polar to get into the CNS, it is
not an effective antihypertensive agent.

H Cl
N Clonidine: R= H
N R 4-Hydroxyclonidine: R= OH
N
H Apraclonidine: R= NH2
Cl
 Apraclonidine and Brimonidine
• Both are selective α2-receptor agonists.
Br N H Cl
H
H Cl N N
N Clonidine: R= H N N N
N R 4-Hydroxyclonidine: R= OH N N
N H H
Apraclonidine: R= NH2 N N
H Cl S
Brimonidine Tizanidine
 Tizanidine
• Tizanidine finds use in treating spasticity
associated with multiple sclerosis or spinal cord
injury. By stimulating α2-adrenergic receptors, it is
believed to decrease the release of excitatory
amino acid neurotransmitters from spinal cord
inter-neurons.

Br N H Cl
H
H Cl N N
N Clonidine: R= H N N N
N R 4-Hydroxyclonidine: R= OH N N
N H H
Apraclonidine: R= NH2 N N
H Cl S
Brimonidine Tizanidine
 Guanabenz and Guanfacine
• Structurally, these analogues of clonidine can be
considered "open-ring imidazolidines". In these
compounds, the 2,6-dichlorophenyl moiety found in
clonidine is connected to a guanidino group by a two-
atom bridge.
• In the case of guanabenz, this bridge is a —CH=N—
group, while for guanfacine it is a —CH2CO—moiety.
For both compounds, conjugation of the guanidino
moiety with the bridging moiety helps to decrease the
pKa of this normally very basic group so that at
physiological pH a significant portion of each drug
exists in its nonionized form.
 Guanabenz and Guanfacine
Clonidine Guanfacine Guanabenz
Elimination half-life 20-25 17 6
(hours)
Excreted unchanged 60 50 Very little
in the urine (%)

NH2
H2N Cl HN O Cl
H Cl
NH HN
N HN HC H2C
N
N
H Cl Cl
Cl
Clonidine Guanabenz Guanfacine
 Methyldopa
• The presence of an α-methyl group in the correct
configuration on the phenylethylamine nucleus yields
compounds with increased potency at α2-receptors and
decreased potency at α1-receptors.
• Although α-methylnorepinephrine is not given as a drug, it
is the metabolic product of the drug methyldopa.
N+H3 Cl- NH2
HO HO
COOEt Esterases COOH L-Aromatic amino acid
H3C H3C
HO HO decrboxylase
Methyldopate Methyldopa

H
NH2 OH
HO HO 1 NH2
H Dopamine −hydroxylase 2
H3C H3C
H
HO HO
−Methyldopamine (R ,2S ) -−Methylnorepinephrine
• It is postulated that α-methylnorepinephrine acts
on α2-receptors in the CNS in the same manner as
clonidine, to decrease sympathetic outflow and
lower blood pressure.
N+H3 Cl- NH2
HO HO
COOEt Esterases COOH L-Aromatic amino acid
H3C H3C
HO HO decrboxylase
Methyldopate Methyldopa

H
NH2 OH
HO HO 1 NH2
H Dopamine −hydroxylase 2
H3C H3C
H
HO HO
−Methyldopamine (R ,2S ) -−Methylnorepinephrine
 Methyldopa
• Methyldopa is used only by oral administration since
its zwitterionic character limits its solubility.
• Absorption can range from 8-62% and appears to
involve an amino acid transporter. Absorption is
affected by food, and about 40% of that absorbed is
converted to methyldopa-O-sulfate by the mucosal
intestinal cells.
• Entry into the CNS also appears to involve an active
transport process.
 Methyldopate (Aldomet ester)
• The ethyl ester hydrochloride salt of methyldopate,
was developed as a highly water-soluble derivative
that could be used to make parenteral
preparations.
N+H3 Cl- NH2
HO HO
COOEt Esterases COOH
H3C H3C
HO HO
Methyldopate Methyldopa