PHAR2811
Lecture
Amino acids as drug targets
COMMONWEALTH OF AUSTRALIA
Copyright Regulation
WARNING
This material has been reproduced and communicated to you by
or on behalf of the University of Sydney pursuant to Part VB of
the Copyright Act 1968 (the Act).
The material in this communication may be subject to copyright
under the Act. Any further reproduction or communication of this
material by you may be the subject of copyright protection under
the Act.
Do not remove this notice
Amino Acid derivatives
•
•
•
•
•
•
Adrenalin/epinephrine
Serotonin
GABA
Histamine
Dopa & dopamine
thyroxin
The Catecholamine Family
• L-dopa
• Dopamine
• Noradrenalin or
Norepinephrine
• Adrenalin or
epinephrine
OH
OH
Catechol
The Catecholamine Family
O
O
H3N+
CH
C
H3N+
O-
CH 2
CH 2
Tyrosine
hydroxylase
OH
Tyrosine
CH
HO
OH
L-Dopa
C
O-
The Catecholamine Family
CH 3
+NH3
CH 2
decarboxylation
CH 2
hydroxylation
HO
+NH3
+NH2
CH 2
CH 2
CH
HO
HO
OH
L-Dopamine
HO
methylation
CH
HO
OH
Noradrenalin
OH
Adrenalin
The Catecholamine Family
• Family members act as neurotransmitters
in the brain and hormones in the
circulatory system
• Produced in adrenal medulla and
sympathetic neurons
• The pools are kept separate by the blood
brain barrier
Acting as hormones
• The flight or fight response
• Adrenalin and noradrenalin are produced
in the adrenal medulla and stored in
granules
• Released into the circulation by stimuli
from the sympathetic nervous system
• They bind to specific receptors
Adrenergic receptors
• Glycoproteins which span the membrane
• Known as G-coupled protein receptors
• 4 classes of adrenergic receptors: a1, a2,
b1, b2
• Some are stimulatory (β) some inhibitory
(α)
• Activate or inhibit adenylyl cyclase 
cAMP
Adrenergic receptors
• Have short term and long term effects
• The alpha receptors stimulate smooth
muscle contraction in peripheral organs
• the beta receptors mobilise fuels, relax
smooth muscles of the bronchi and blood
vessels supplying skeletal muscles and
increase heart rate.
Adrenergic receptors
• The end result of these actions is to
mobilise and shunt energy reserves to
where they are most needed
• prepare for action!
Used as a drug: Adrenalin
• Treatment for cardiac arrest and
anaphylactic reactions
• Bronchodilator properties used in asthma
• Agonists and antagonists to
adrenergic receptors are also used
as drugs
Acting as neurotransmitters
• Noradrenalin is uniquely found between
the junctions of sympathetic neurons and
smooth muscle cells
• Decreased levels of noradrenalin in the
brain are associated with some forms of
clinical depression
Noradrenalin and depression
Strategies to increase noradrenalin levels in
the brain:
• Inhibit inactivation (monoamine oxidase
inhibitors or MAO inhibitors)
OR
• Inhibit reuptake (tricyclics)
Other Catecholamines
• L-dopa and dopamine
• Dopamine is also a neurotransmitter in
synapses in localised areas of the brain
stem
• Parkinson’s disease is caused from the
degeneration of these dopaminergic
neurons.
• The psychotic symptoms of Schizophrenia
are associated with elevated dopamine
Parkinson’s disease
• Parkinson patients are treated with L-dopa or
levadopa
• Although it is dopamine that is deficient it cannot
cross the blood brain barrier
• L-dopa crosses the barrier (on amino acid transporters),
where it is decarboxylated to produce dopamine
• It is usually administered with a peripheral
decarboxylase inhibitor; carbidopa (to prevent the LDopa going to dopamine before it gets to the brain).
L-Dopa and dopamine
+NH3
O
H3N+
CH
CH 2
Crosses the
blood brain
barrier
HO
OH
L-Dopa
C
O-
CH 2
CH 2
decarboxylation
This reaction
must be inhibited
before it gets to
the blood brain
barrier
HO
OH
L-Dopamine
carbidopa
HNH 2N
CH 3
O
C
C
O
OH
H3N+
CH 2
HO
CH
CH 2
HO
OH
Carbidopa, an inhibitor of
levadopa decarboxylation
OH
L-Dopa
C
O-
Tyrosine Hydroxylase (TH)
• The rate limiting step in the pathway
• Adding another –OH to the aromatic ring
• It requires O2 and biopterin (this moiety also
makes up folates – we obtain it from our diet or
microorganisms in the gut)
• This is a tricky reaction
• There are only a few examples of this in
life!
Tyrosine Hydroxylase
O
O
H3N+
CH
CH 2
C
H3N+
O-
OH
Tyrosine
CH 2
O2
Tyrosine
hydroxylase
CH
HO
OH
L-Dopa
C
O-
Biopterin
H2N
H
N
N
OH
N
OH
O
CH 3
N
H
OH
Tyrosine hydroxylase
• Although it is the rate limiting step in
synthesis it is not a great site for drug
action.
• There are drugs that inhibit the enzyme
but these are rarely used
• Regulation of adrenalin is done at the
release phase
• Most drugs work on the receptor
Tyrosine hydroxylase
• There are 3 isoforms produced by
alternative splicing although the biological
significance of these is not entirely clear.
• Another example of a similar reaction is
the conversion of phenylalanine to tyrosine
• The enzyme here is phenylalanine
hydroxylase
• This reaction also requires biopterin
Phenylketonuria (PKU)
• The conversion of phenylalanine to
tyrosine is a similar hydroxylation
• Catalysed by phenylalanine hydroxylase
• If this enzyme is defective the
phenylalanine has to go elsewhere
• Accumulates as phenylpyruvate
Phenylalanine hydroxylase
O
H3N+
CH
C
O
O-
O2
CH 2
H3N+
CH
CH 2
Phenylalanine
hydroxylase
Phenylalanine
OH
Tyrosine
C
O-
PKU: diversion
O
H3N+
CH
C
CH 2
O
O-
Oxidative
deamination
O
C
C
CH 2
Build up causes
severe mental
retardation in
developing brain
Phenylalanine
Phenylpyruvate
O-
PKU diet
Thyroxin
I
I
+NH3
HO
H2
C
O
CH
C
I
I
O-
Synthesised from 2 tyrosine residues
O
Thyroxin
Protein,
thyroglobulin
CH 2
N
OH
HO
C
H2
C
Thyroxin
CH 2
I
I
OH
I
Iodination
Oxidative
coupling
H2
C
HO
I
I
I
+NH3
Thyroxin
HO
H2
C
O
CH
C
I
I
I
I
O
O-
+NH3
HO
H2
C
O
CH
C
I
O
I
O-
I
I
+NH3
HO
I
O
O
CH
C
I
I
proteolysis
HO
H2
C
O
I
O-
CH 2
I
I
+NH3
I
I
HO
H2
C
O
CH
C
I
O
I
O-
I
I
+NH3
HO
H2
C
O
CH
C
I
I
O-
5 – 6 thyroxins
released per
thyroglobulin
O
Hypothyroidism:
• thyroxin levels too low;
individuals present with
lethargy, cold skin and
often overweight.
• low iodine in the diet
often the result of low
iodine in the
soil….leads to a goiter
Cretinism
• Thyroxin is
essential for
normal growth and
development
• A deficiency will
result in cretinism,
a condition defined
by mental
retardation,
stunted growth
Serotonin
• A derivative synthesised
by the decarboxylation of
tryptophan.
• A neurotransmitter
• low levels of serotonin
have also been linked to
depression.
• Prozac acts to inhibit the
degradation of serotonin.
Synthesis of Serotonin
O
H3N+
CH
C
O-
H3N+
CH 2
CH 2
CH 2
OH
HN
HN
Tryptophan
Serotonin
Histamine
• Produced by the decarboxylation of
histidine
• A common product of allergic reactions,
produced by mast cells
• Neurotransmitter
• Involved in sleep regulation
• Regulates acid secretions in the stomach
• Antihistamines are used to relieve the
symptoms of an allergic reaction
Histamine synthesis
O
H3N+
CH
C
O-
H3N+
CH 2
CH 2
N
decarboxylation
NH
Histidine
CH 2
N
NH
Histamine
GABA
• Gamma amino butyric acid
• Produced by the decarboxylation of
glutamate
• Major inhibitory neurotransmitter
• Released by 30% of synapses
GABA synthesis
O
H3N+
CH
C
+NH3
O-
CH 2
CH 2
CH 2
CH 2
CH 2
C
OH
Glutamate
O
Decarboxylation
C
OH
GABA
O
Amino Acid derivatives
•
•
•
•
•
•
Adrenalin/epinephrine
Serotonin
GABA
Histamine
Dopa & dopamine
thyroxin