This document discusses adrenergic receptors and their role in the sympathetic nervous system. It covers topics such as: 1) The two types of adrenergic receptors (alpha and beta) and their subtypes which are G-protein coupled receptors. 2) The distribution of adrenergic receptors in different tissues and the effects of activating them, such as contraction of cardiac muscle from beta 1 receptor activation. 3) The biosynthesis pathway of norepinephrine and epinephrine from tyrosine and their metabolism by monoamine oxidase and catechol-O-methyltransferase. 4) Potential drug targets for regulating the adrenergic system, including receptors, transporters, enzymes

1. © Oxford University Press, 2013
ADRENERGICS
Patrick: An Introduction
to Medicinal Chemistry 6e
Chapter 23

2. © Oxford University Press, 2013
1. Nerve transmission
Peripheral nervous system
Peripheral nerves
Muscle
Gastro-
intestinal
tract
(GIT)
Brain
Spinal cord
CNS
Heart

3. © Oxford University Press, 2013
1. Nerve transmission
Peripheral nervous system
CNS
(Somatic)
CNS
(Autonomic)
Sympathetic
Parasympathetic
NA
Ach
Synapse
NR
Ach
Ach Ach
Adrenal
medulla
Adrenaline
Skeletal
muscle
Synapse
AUTONOMIC
Smooth muscle
Cardiac muscle
Ach = Acetylcholine
NA = Noradrenaline
AR = Adrenergic receptor
NR = Nicotinic receptor
MR = Muscarinic receptor
(NR)
MR & AR
(NR)
Ach AR
NR
MR

4. © Oxford University Press, 2013
2. Adrenergic receptors (adrenoceptors)
Notes
•Two types of adrenoceptor (a and b)
•Subtypes (a1 and a2; b1, b2 and b3)
•Subtypes of subtypes (a1A a1B a1D a2A a2B a2C)
•G-protein coupled receptors
Signal transduction
a1-adrenoceptor
Generates inositol triphosphate and diacylglycerol
a2-adrenoceptor
Inhibits generation of cyclic AMP
b1, b2 and b3-adrenoceptors
Generate cyclic AMP

5. © Oxford University Press, 2013
2. Adrenergic receptors (adrenoceptors)
Distribution
and effects
Organ or tissue Predominant adrenoceptors Effect of activation Physiological effect
Heart muscle 1 Muscle contraction Increased heart rate and force
Bronchial smooth muscle 1 Smooth muscle contraction Closes airways
2 Smooth muscle relaxation Dilates and open airways
Arteriole smooth muscle (not
supplying muscles)
Smooth muscle contraction Constricts arterioles and
increases blood pressure
(hypertension)
Arteriole smooth muscle
(supplying muscles)
2 Smooth muscle relaxation Dilates arterioles and increases
blood supply to muscles
Veins Smooth muscle contraction Constricts veins and increases
blood pressure (hypertension)
2 Smooth muscle relaxation Dilates veins and decreases
blood pressure (hypotension)
Liver 2 Activates enzymes which
metabolise glycogen and
deactivates enzymes which
synthesise glycogen
Breakdown of glycogen to
produce glucose
GI tract smooth muscle Relaxation Shuts down digestion
Kidney 2 Increases renin secretion Increases blood pressure
Fat cells 3 Activates enzymes Fat breakdown

6. © Oxford University Press, 2013
2. Adrenergic receptors (adrenoceptors)
Distribution and effects
Activating a-adrenoceptors generally contracts smooth muscle (except gut)
Activating b2-adrenoceptors relaxes smooth muscle
Activating b1-adrenoceptors contracts cardiac muscle
b2-Adrenoceptors predominate in the airways
b1- Adrenoceptors predominate in the heart
Receptors are distributed differently in different organs and tissues
Receptor-selective drugs act selectively at different organs and tissues

7. © Oxford University Press, 2013
3. Chemical messengers
Noradrenaline - neurotransmitter
HO
HO
NH2
R
OH
H
Adrenaline - hormone
HO
HO
NHMe
R
OH
H
H
O
H
O
N
HR
O
H
H
H
O
H
O
N
HR
O
H
H
Alkylamine
Catechol
General structure of catecholamines
H
O
H
O
N
HR
O
H
H

8. © Oxford University Press, 2013
4. Biosynthesis
Notes
•Pathway controlled by regulation of tyrosine hydroxylase
•Inhibited by noradrenaline - feedback control
L-Tyrosine
HO
NH2
CO2H
H
L-Tyrosine Levodopa
HO
HO
NH2
CO2H
H
Tyrosine
hydroxylase
Levodopa Dopamine
HO
HO
NH2
Dopa
decarboxylase
Dopamine
Noradrenaline
HO
HO
NH2
OH
H
Noradrenaline
Dopamine
b-hydroxylase
Noradrenaline
Adrenaline
HO
HO
NHMe
OH
H
N-Methyl
transferase
Adrenal
medulla
Adrenaline

9. © Oxford University Press, 2013
5. Metabolism of noradrenaline
MAO = Monoamine oxidase
COMT = Catechol O-methyltransferase
HO
HO
NH2
No r a d r e n a l i n e
OH
H
Noradrenaline
HO
HO
NH2
N o r a d r e n a l i n e
OH
H
Noradrenaline
MeO
HO
NH2
OH
H
COMT
HO
HO
O
OH
OH
H
HO
HO
O
H
OH
H
MAO
M
eO
HO
O
H
OH
H
MAO
Vanillylmandelic acid
COMT
Vanillylmandelic acid

10. © Oxford University Press, 2013
Neurotransmitter repackaged or
metabolized
Target
cell
Receptor binding and new signal
Target
cell
6. Transmission process
.
.
.
nerve signal
.
.
. Target
cell
.
Receptor Vesicle containing
noradrenaline
.
Transport protein
Vesicles fuse and release transmitter
nerve signal
Target
cell
.
.
. Signal
Neurotransmitter reabsorbed
by active transport
Target
cell
.
.
Neurotransmitter departs receptor
Target
cell

11. © Oxford University Press, 2013
6. Transmission process
Presynaptic Control
•Presynaptic receptors control release of noradrenaline
•Prostaglandins, acetylcholine and noradrenaline affect release
•Active cholinergic nervous system inhibits adrenergic activity
Ach
NA
NA
Smooth muscle
Prostaglandins
Cholinergic receptor
Presynaptic adrenergic receptor
Activation of target receptor
reduces noradrenaline release
Prostaglandin receptor
Postsynaptic adrenergic receptor
NA Noradrenaline

12. © Oxford University Press, 2013
7. Drug targets
Noradrenaline
Adrenergic receptor
Transport protein
Presynaptic receptor
1. Enzymes in the biosynthesis of noradrenaline
.
Tyr
1 3
.
3. Exocytosis of vesicles with cell membrane
2
.
2. Vesicles carrying noradrenaline
4
.
4. Adrenergic receptor
5 .
5. Transport protein for noradrenaline
6
Metabolites
6. Metabolic enzymes
7
7. Presynaptic receptors

13. © Oxford University Press, 2013
O
H
O
H
Ser-207
Ser-204
TM5
Phe-290
CO2
TM6
Asp-113
TM3
O
.
.
.
.
..
..
Asn-293
C NH2
.
. ..
8. Adrenergic binding site
+
O
O
H
H N
CH3
O
H
H
H

14. © Oxford University Press, 2013
9. Structure-Activity Relationships
Notes
•Phenol groups form H-bonds to binding site (especially b-adrenoceptors)
•meta-Phenol can be replaced with other hydrogen bonding groups
•Alcohol forms a hydrogen bond to the binding site
•Aminium ion forms an ionic bond to the binding site
•N-Alkyl groups affect target selectivity
•Larger N-alkyl groups lead to selectivity for b-adrenoceptors
•Aromatic ring forms van der Waals interactions with the binding site
Alcohol
Aminium ion
Phenol
Phenol