CHAPTER II

DRUGS ACTING ON NEUROTRANSMITTERS AND THEIR RECEPTORS

OVERVIEW OF RELEVANT NEUROANATOMY

AND NEUROPHYSIOLOGY
This chapter deals with endogenous messenger molecules
(neurotransmitters) within the human central and peripheral
nervous systems (CNS, PNS), their targets, and the drugs
that affect them. Since most of these messengers act on
nerve cells (neurons), it is appropriate to review the anatomy
and physiology of the nervous system and to discuss briefly
the neuronal networks that can be manipulated
therapeutically.

Lecture 5

Nerve Conduction

Repolarisation. At a certain point, the depolarisation of the membrane

causes the sodium channels to close. As a result the potassium
channels open for 0.5ms, causing potassium ions to rush out, making
the inside more negative again. Since this restores the original
polarity, it is called repolarisation. As the polarity becomes restored,
there is a slight overshoot in the movement of potassium ions (called
hyperpolarisation). The resting membrane potential is restored by the
Na+K+ATPase pump.

Depolarisation. A stimulus can cause the membrane potential to change a

little. The voltage-gated ion channels can detect this change, and when the
potential reaches 30mV the sodium channels open for 0.5ms. The causes
sodium ions to rush in, making the inside of the cell more positive. This phase
is referred to as a depolarisation since the normal voltage polarity (negative
inside) is reversed (becomes positive inside).

Ion channel

Synaptic Transmission

Fig. Action potential of a neuron

Nerve impulses
Impul adalah sinyal listrik yang bergantung pada aliran ion yang menembus
membran plasma neuron.

Nerve impulses
Impul adalah sinyal listrik yang bergantung pada aliran ion yang menembus
membran plasma neuron.

Nerve impulses
Impul adalah sinyal listrik yang bergantung pada aliran ion yang menembus
membran plasma neuron.
Myelin sheath - Only vertebrates have a myelin sheath surrounding their neurones.
The voltage-gated ion channels are found only at the nodes of Ranvier, and between
the nodes the myelin sheath acts as a good electrical insulator. The action potential
can therefore jump large distances from node to node (1mm), a process that is called
saltatory propagation. This increases the speed of propagation dramatically, so
while nerve impulses in unmyelinated neurones have a maximum speed of around
1 m/s, in myelinated neurones they travel at 100 m/s.

Synaptic Transmission
Synaptic transmission is the process
whereby neurons communicate with each
other and with the target organs whose
physiology they are influencing; synaptic
transmission permits the action potential to
jump from one neuron to the next.

10

It is imperative that the medicinal chemist

understands synaptic transmission when
designing neuroactive drugs. Synaptic
transmission is not electrical but chemical,
and is triggered by the arrival of the action
potential at the nerve ending.

11

This causes a Ca2+ ion influx across the

membrane and into the neuron, resulting in
the release of an interneuronal chemical
messenger (neurotransmitter) characteristic
for that particular neuron. There seem to be
several different neurotransmitter release
mechanisms, although none is well
understood..
12

When
released,
the
neurotransmitter
crosses the synaptic gap by passive
diffusion and binds transiently to a receptor
on the membrane of the postsynaptic
neuron. This receptor occupation initiates
the electrical axonal wave of depolarization
of
the
next
(postsynaptic)
neuron;
alternatively, it can trigger the activation of
an enzyme such as adenylate cyclase and
the formation of cAMP as a second
messenger.
13

Acetylcholine and The Cholinergic Receptors

HO

H
N
N

CH3

Nicotine

H3C

H2
C N(CH3)3

Cis-L-(+)-muscarine

Cholinergic Agonist
HO

H
N
N

CH3

Nicotine

H3C

H2
C N(CH3)3

Cis-L-(+)-muscarine

Fig. The principal direct-acting cholinergic agonists

Carbachol is a very potent agent because it is not

an ester but a carbamate, and is hydrolyzed slowly.
It is used in glaucoma to reduce intraocular
pressure.
Bethanechol also has a prolonged effect, and finds
application in stimulation of the gastrointestinal tract
and urinary bladder (both muscarinic effects) to
relieve postoperative atony.
17

Acetylcholin Metabolism
Acetylcholin is synthesized by the reaction

Cholin + Acetyl-CoA Acetylcholin + CoA-SH

which is catalyzed by choline acetyltransferase. Acetyl-Coenzyme A (CoA)
is ubiquitous; cholin is obtained from phosphatidylcholin (lecithin) and
free cholin.
Some of this choline is recycled after Ach is hydrolyzed by
esterase (AChE), terminating the neuronal impulse.

acetylcholine

18

CHOLINERGIC BLOCKING AGENTS

Drugs that inhibit the interaction of ACh with the AChR are cholinergic
blocking agents ( or parasympatholytics ) .

CH3

N
CH2OH

()Atropin
(-)Hyosciamine
19

CH3

N
CH2OH

Scopolamine

20

CH3

OH
O

Homatropine

21

H3C

CH3
CH

H2
C

C
H

N CH

CH3
CH3

CH2

Cl
Propantheline chloride

22

GANGLIONIC BLOCKING AGENTS

Ganglionic blocking agents interfere with the nicotinic ACh
receptor in the ganglia

H3C

H2
C

N(C2H5)3

Tetraethylammonium salts

23

(H3C)3N

(CH2)6

N(CH3)3

Hexamethonium

24

NEUROMUSCULAR BLOCKING AGENTS

Neuromuscular blocking agents are widely used in surgery.
They are capable of relaxing the abdominal muscles without
using deep anesthesia, and make surgery much easier for both
the surgeon and patient
CH3
HN

OCH3

HO

H2
C

O
H2C

N
H3CO

H3C

CH3

HO

Tubocurarine

25

CH3
N

CH3

H3 C

CH3

Pancuronium
26

The depolarizing neuromuscular blocking agents were discovered

through mimicking the N+ - N+ distance described above with aliphatic
compounds
This drug binds normally to the AchR and triggers the same response
as Ach, a brief contraction of the muscle, which, however, is followed
by a prolonged period of transmission blockage accompanied by
muscular paralysis

CH3

CH3

H3C

(CH2)10

CH3

CH3

CH3

Decamethonium
27

CH3
H3C

CH2 CH2

H3C

CH2

CH3
H3C

H2
C

H2
C

CH2

CH3

C
O

Succinylcholin

28

O2N

H2
C

CH2
N

CH2

CH3

(CH2)4

O2 N

H2
C

CH2
N

CH2

CH3

p-nitrobenzyl-hexamethonium

29

ANTICHOLINESTERASE
DRUGS
Anticholinesterase drugs are compounds
that block AChE and inhibit the destruction
of released ACh.

30

Acetylcholinesterase inhibitors can act by ether of two mechanisms:

1.As classical competitive enzyme inhibitors they have a high affinity for the
active site, but not substrates. The enzymes is occupied by the inhibitor for
relatively long periods, and therefore can not handle ACh efficiently, do to
saturation phenomenon.
2.The inhibitor acylates the serine hydroxyl of ACh, forming an ester more
stabile than acetate, such as a carbamate or phosphate, The hydrolysis of
these esters takes a long time even if they are not irreversible, as formerly
thought. Acetylcholine cannot then be hydrolyzed, since the active site is
covalently occupied.

31

A representative of the first group of inhibitors is edrophonium, a

short acting drug that binds to the anionic site of the enzymes
and also forms a hydrogen bond with the imidazole nitrogen of
the active site

CH3
HO

CH3
C2 H5

Cl

32

Ambenonium also does not react covalently with the enzyme but has a
much longer duration of action than edrophonium.
Cl
C2H5

H
N

C
H2

C
H2

C2H5
C2 H5

H
N

H2
C

H2
C

C2H5
Cl

33

Mechanism of acetylcholine hydrolysis by acetylcholinesterase

34

H2C

Ser

AChE

H
N
N

His

35

H2C

H3C
N
H3C

C
H2

H3C

CH3
H2
C

Ser

C
O

AChE

H
N
N

His

36

H2C

CH3

H3C
N
H3C

H3C

C
H2

O
C

H2
C

Ser

OH

AChE

N
N

His

37

H2C

CH3

H3C
N
H3C

C
H2

H2
C

H3C
OH

Ser

O
O

AChE

C
N

His

Choline

38

H2C

H3C

Ser

O
O

AChE

CH3COOH

N
N

H2O

His

39

The second group of AChE inhibitors is represented by alkaloid

physostigmine (eserin), isolated from the seeds of Physostigma
venenosum, the Calabar bean
CH3

H2N C O

O
N

CH3

CH3

Physostigmine

Synthesis analoques, like neostigmine and its congeners, are also active.
H3C
N

H3C

N(CH3)2

O
Neostigmine

40

Uncharged carbamates, like carbaryl (sevin) can penetrate the CNS of

insects and act quite selectively as insecticides with a low toxicity to
mammals
O

H
N

CH3

Sevin
O
O

O CH

H
N CH3
CH3
CH3

Propoxur (Baygon).
= isopropoxy phenyl methyl carbamat
41

Even longer acting covalent AChE inhibitors are the organophosphate

esters, such as echothiophate, developed from nerve gas discovered
but never used in World War II.

C2H5O

P
C2H5O

CH2

CH2

N(CH3)3

Echothiophate
Many useful insecticides can also be found in this group. Malathion is
a pro-drug, since the carried out by insects but not mammals.
O

P
H3CO

Malaoxon

H3CO

H
C

COOC2H5

COOC2H5

Malathione

42

Both groups of AChE inhibitor are used

therapeutically. One use is in glaucoma, in
which high intraocular pressure can lead to
permanent damage to the optic disc,
resulting in blindness. The local instillation
of physostigmine or echothiophate solution
in the eye results in a long-lasting decrease
in the intra ocular pressure as well as
myosis (contraction of the pupil).

43

1. The other use of anticholinesterase drugs is in

m y a s t h e n i a
g r a v i s. This is an
autoimmune
disease
caused
by
the
development of antibodies against the patients
own Ach receptors, accompanied by disturbed
neuromuscular transmission.
2. Acetylcholinesterase inhibitors will increase the
Ach concentration and excitation of the
neuromuscular junction, resulting in increased
strength and endurance.

44

As expected, AChE inhibitors are also potent curare antidotes,

because the increased Ach levels displace the blocker more readily.

Mode of action of pralidoxime, an acetylcholinesteraseinhibitor antidote

45

Atropine is also administered to victims of

organophosphate poisoning, to relieve peripheral and
central muscarinic symptoms due to excessive Ach.

46

The ClinicalMolecular Interface: Alzheimers

Dementia as a Cholinergic Disorder
Alzheimers disease is a common neurological
disorder affecting approximately 20% of
persons over the age of 80 years. Clinically,
Alzheimers is characterized by loss of short-term
memory, impaired cognition, decline in intellectual
function, and decreased ability to carry out the
activities of daily life.

47

At the gross anatomical level, Alzheimers disease is

brain atrophy and loss of the

outer gray matter of the cerebral cortex. At
associated with

the cellular level, the histopathology of Alzheimers reveals

plaques and tangles, where plaques are composed of amyloid peptide and tangles are composed primarily of
phosphorylated tau protein. It is believed that the
accumulation of neurotoxic aggregates of -amyloid peptide
is concomitantly linked with degeneration of cholinergic
pathways in the CNS. This degeneration subsequently leads
to progressive regression of memory and learned functions
and to the other symptoms of Alzheimers disease.

48

Therapeutic approaches to Alzheimers disease initially targeted

the cholinergic systems. In early work, drug treatment with either
choline replacement or cholinergic agonists was of negligible value.
However,

cholinesterase enzyme inhibitors

such as donepezil (4.28), rivastigmine (4.29), and

galantamine (4.30) are of definite symptomatic value

in the treatment of Alzheimers disease .

49

O
Rivastigmine

C4H6 O6

51

By inhibiting the catabolic breakdown of

acetylcholine, these agents prolong the effective
half-life of acetylcholine as a neurotransmitter,
thereby alleviating some of the symptoms of the
disease. About 70% of people show

time-limited improvement in their

memory when on these agents.
52

Unfortunately, these agents are only symptomatic and do

not treat the underlying cause, namely the accumulation
of neurotoxic -amyloid aggregates. Future research in
Alzheimers disease is targeting other potential receptors,
such as by blocking the synthesis of -amyloid by
inhibiting the secretase enzyme system involved in the
conversion of amyloid precuror protein to -amyloid, or by
binding to -amyloid and inhibiting its aggregation into a
neurotoxic form. Since the average age of the

population is on the increase, the frequency of

Alzheimers disease is increasing rapidly and
requires urgent attention.

53