Transcript Slides PPT - The University of Sydney

PHAR2811
Lecture
Amino acids as drug targets
COMMONWEALTH OF AUSTRALIA
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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