Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 19
CHOLINERGICS, ANTICHOLINERGICS
& ANTICHOLINESTERASES
Part 2: Cholinergics & anticholinesterases
©1
Contents
Part 2: Cholinergics & anticholinesterases
12. Cholinergic Antagonists (Muscarinic receptor) (2 slides)
12.1.
Atropine
12.2.
Hyoscine (scopolamine)
12.3.
Comparison of atropine with acetylcholine
12.4.
Analogues of atropine
12.5.
Simplified Analogues (2 slides)
12.6.
SAR for Antagonists (3 slides)
12.7.
Binding Site for Antagonists (2 slides)
13. Cholinergic Antagonists (Nicotinic receptor)
13.1.
Curare (2 slides)
13.2.
Binding
13.3.
Analogues of tubocurarine (5 slides)
[22 slides]
©1
12. Cholinergic Antagonists (Muscarinic receptor)
•
•
•
Drugs which bind to cholinergic receptor but do not activate it
Prevent acetylcholine from binding
Opposite clinical effect to agonists - lower activity of
acetylcholine
Postsynaptic
nerve
Postsynaptic
nerve
Ach
Ach
Ach
Antagonist
©1
12. Cholinergic Antagonists (Muscarinic receptor)
Clinical Effects
• Decrease of saliva and gastric secretions
• Relaxation of smooth muscle
• Decrease in motility of GIT and urinary tract
• Dilation of pupils
Uses
• Shutting down digestion for surgery
• Ophthalmic examinations
• Relief of peptic ulcers
• Treatment of Parkinson’s Disease
• Anticholinesterase poisoning
• Motion sickness
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.1 Atropine
Me
N
easily racemised
H
CH2 OH
O
CH
C
*
O
•
•
•
•
•
•
Racemic form of hyoscyamine
Source - roots of belladonna (1831) (deadly nightshade)
Used as a poison
Used as a medicine
decreases GIT motility
antidote for anticholinesterase poisoning
dilation of eye pupils
CNS side effects – hallucinations
©1
Link
• Opthalmic use of atropine a as mydriatic (dilating) agent
has been largely replaced by use of analogs tropicamide
and cyclopenatolate (vida infra).
• However, atropine, and its chiral analog hyoscyamine,
are utilized to treat gastrointestinal disorders
• Also these antagonists can be used to treat the symptoms
of an excess of acetylcholine, such as might occur upon
exposure to an inhibitor of the enzyme acetylcholinesterase
©1
(such as a nerve gas). Link
• Atropine is also used to avoid bradycardia (too slow heart rate) during some
procedures (such as pediatric RSI, rapid sequence intubation), which also use
succinylcholine (suxamethonium chloride) as a neuromuscular blocking agent
(antagonist at the nicotinic Ach receptors).
• As shown in the diagram above, the atropine serves as an antagonist of acetycholine
at the M2 receptor of the sinoatrial node.
• The acetylcholine at this junction triggers a GPCR using the Gi G-protein, normally
leading to decrease in the levels of cAMP. Thus the atropine restores normal levels of
cAMP, reversing the effects of vagus nerve stimulation.
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.2 Hyoscine (scopolamine)
Me
N
H
O
CH2 OH
H
H
O
CH
C
*
O
•
•
•
Source - thorn apple
Medical use treatment of motion sickness
Used as a truth drug (CNS effects)
©1
Hyoscine (Scopolamine)
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.3 Comparison of atropine with acetylcholine
Me
N NMe3
CH2
CH
H2
CH2 OH
O
O
C
O
•
•
•
•
•
•
CH3
CH
C
O
Relative positions of ester and nitrogen similar in both molecules
Nitrogen in atropine is ionised
Amine and ester are important binding groups (ionic + H-bonds)
Aromatic ring of atropine is an extra binding group (vdW)
Atropine binds with a different induced fit - no activation
Atropine binds more strongly than acetylcholine
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.4 Analogues of atropine
Br
CH3
CH(CH3) 2
H 3C
H 3C
N
NO3
N
H
H
CH2 OH
CH2 OH
O
CH
C
O
Ipratropium
(bronchodilator & anti-asthmatic)
•
•
•
O
CH
C
O
Atropine methonitrate
(lowers GIT motility)
Analogues are fully ionised
Analogues unable to cross the blood brain barrier
No CNS side effects
©1
The combination preparation ipratropium/salbutamol is a formulation containing ipratropium bromide and
salbutamol sulfate (albuterol sulfate) used in the management of chronic obstructive pulmonary disease (COPD)
and asthma. It is marketed by Boehringer Ingelheim as metered dose inhaler (MDI) and nebuliser preparations
under the trade name Combivent.
Medications commonly used in asthma and COPD (primarily R03) edit
Anticholinergics:
Ipratropium, Tiotropium
Short acting β2-agonists: Salbutamol, Terbutaline
Long acting β2-agonists (LABA):
Bambuterol, Clenbuterol, Fenoterol, Formoterol, Salmeterol
Corticosteroids:
Beclometasone, Budesonide, Ciclesonide, Fluticasone
Leukotriene antagonists: Montelukast, Pranlukast, Zafirlukast
Xanthines: Aminophylline, Theobromine, Theophylline
Mast cell stabilizers:
Cromoglicate, Nedocromil
Combination products:
Budesonide/formoterol, Fluticasone/salmeterol, Ipratropium/salbutamol
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Pharmacophore = ester + basic amine + aromatic ring
Et
Me
N
Et
Me
CH
Me
CH2 CH2
CH2
CH2 OH
O
CH
O
HO
C
CH2 CH2N(Et)3
Br
O
CH2CH2 N
C
CH
Me
Me
O
C
Cl
O
Amprotropine
Tridihexethyl bromide
Propantheline chloride
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Me
N
Me2N
N
H
O
CH2CH3
N
CH
O
CH
O
CH
OH
O
CH2OH
Tropicamide
(opthalmics)
Benztropine
(Parkinsons disease)
Cyclopentolate
(opthalmics)
O
HN
N
N
C
N
C
CH2
CH
Benzhexol
(Parkinsons disease)
N
N
Me
O
Pirenzepine
(anti-ulcer)
©1
Tropicamide
Cyclopentolate
• Tropicamide and Cyclopentolate (above) are among the most
commonly employed mydriatic (dilating) and cycloplegic
(paralyzing) agents
• Both function as antagonists at the muscarinic acetylcholine
receptors
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists
R'
O
CH2
R 2N
CH2
R' = Aromatic or
Heteroaromatic
CH
C
R'
O
Important features
• Tertiary amine (ionised) or a quaternary nitrogen
• Aromatic ring
• Ester
• N-Alkyl groups (R) can be larger than methyl (unlike agonists)
• Large branched acyl group
• R’ = aromatic or heteroaromatic ring
• Branching of aromatic/heteroaromatic rings is important
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists
Me
Me
CH
O
O
C
CH2CH2 N
O
Me
CH
C
Me
Me
CH2
O
CH2 CH2NR2
O
Cl
Active
Inactive
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists vs. Agonists
SAR for Antagonists
SAR for Agonists
Tertiary amine (ionised)
or quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups (R) can be
larger than methyl
R’ = aromatic or heteroaromatic
Branching of Ar rings important
Quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups = methyl
R’ = H
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists
van der Waals
binding regions
for antagonists
Acetylcholine
binding site
RECEPTOR SURFACE
©1
12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists
O
Me
O
C
O
O
CH2CH2
Me
CH
N
Me
C
Me
CH
Me
O
O
H2N
CH2
Cl
CH2
NMeR2
CO 2
©1
Asn
13. Cholinergic Antagonists (Nicotinic receptor)
13.1 Curare
• Extract from ourari plant
• Used for poison arrows
• Causes paralysis (blocks acetylcholine signals to muscles)
• Active principle = tubocurarine
MeO
Me
N
HO
Me
H
O
Me
H
H
CH2
CH2
Tubocurarine
O
N
OH
OMe
©1
Tubocurarine chloride is a competitive antagonist of nicotinic neuromuscular
acetylcholine receptors, It is one of the chemicals that can be obtained from curare,
itself an extract of Chondodendron tomentosum, a plant found in South American
jungles which is used as a source of arrow poison. Native indians hunting animals
with this poison were able to eat the animal's contaminated flesh without being
affected by the toxin because tubocurarine cannot easily cross mucous
membranes and is thus inactive orally.
©1
• Tubocurarine began to be
clinically utilized as a surgical
neuromuscular blocking agent in
the 1940’s
• This drug has been supplanted
by safer medicines, but is still
utilized as part of the lethal
injection procedure.
©1
13. Cholinergic Antagonists (Nicotinic receptor)
Pharmacophore
• Two quaternary centres at specific separation (1.15nm)
• Different mechanism of action from atropine based antagonists
• Different binding interactions
Clinical uses
• Neuromuscular blocker for surgical operations
• Permits lower and safer levels of general anaesthetic
• Tubocurarine used as neuromuscular blocker but side effects
©1
13. Cholinergic Antagonists (Nicotinic receptor)
13.2 Binding
protein complex
(5 subunits)
diameter=8nm
S
N
8nm
N
9-10nm
a) Receptor dimer
b) Interaction with tubocurarine
N
N
Tubocurarine
Acetylcholine binding site
©1
13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Me3N(CH2) 10NMe3
Decamethonium
•
•
•
•
Long lasting
Long recovery times
Side effects on heart
No longer in clinical use
©1
Me3NCH2CH2
O
O
O
C
C
CH2 CH2
O
CH2 CH2NMe3
Suxamethonium
(Succinylcholine)
•
•
•
•
•
Esters incorporated
Shorter lifetime (5 min)
Fast onset and short duration
Frequently used during intubation
Side effects at autonomic ganglia
©1
13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
O
Me
Pancuronium (R=Me)
Vecuronium (R=H)
Me
O
Me
N
H
N
Me
H
H
O
H
O
•
•
•
•
•
Me
Steroid acts as a spacer for the quaternary centres (1.09nm)
Acyl groups are added to introduce the Ach skeleton
Faster onset then tubocurarine but slower than suxamethonium
Longer duration of action than suxamethonium (45 min)
No effect on blood pressure and fewer side effects © 1
• Pancuronium is used to block the neuromuscular junction during
surgery or intubation.
• In the US, pancuronium (pavulon) is the second of three drugs used
in execution by lethal injection
• Lawsuits against the lethal injection procedure have charged that
this drug would make the patient unable to cry out if he was in pain, as
might occur if insufficient sodium thiopentol (the anesthetic) had been
©1
administered
13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
MeO
Me
N
MeO
CH 2
Atracurium
OMe
OMe
•
•
•
•
•
•
•
CH 2
O
O
C
C
O
(CH 2)5
O
OMe
H
CH 2
CH 2
N
OMe
MeO
OMe
Design based on tubocurarine and suxamethonium
Lacks cardiac side effects
Rapidly broken down in blood both chemically and metabolically
Avoids patient variation in metabolic enzymes
Lifetime is 30 minutes
Administered as an i.v. drip
Self destruct system limits lifetime
©1
13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Me
N
CH2
R
CH
H
-H
C
Me
N
R
H2C
O
Ph
O
Ph
ACTIVE
CH C
INACTIVE
Atracurium stable at acid pH
Hofmann elimination at blood pH (7.4)
©1
• An improved version of atracurium is the purified form of just one of the ten
possible stereoisomers, that has the highest efficacy and least side effects
• The name of the blocking agent is cisatracurium (NIMBEX)
• This is the most widely used agent surgically.
• 80% of the drug is metabolized via Hofmann elimination, thus lowering variability
in patients with possible liver or renal disease.
• The Hofmann degradation is only dependent on the pH and temperature of the
plasma.
©1
13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Mivacurium
MeO
Me
N
OMe
O
O
O
MeO
N
OMe
O
H3C
OMe
MeO
OMe
OMe
•
•
Faster onset (2 min)
Shorter duration (15 min)
©1
• The use of mivacurium has declined in recent years, in
favor of other agents with better overall profile.
©1
Assigned Reading
Introduction to Medicinal Chemistry by Graham L.
Patrick, Chapter 19, pp 558-590
Bowman, W. C.. Neuromuscular block. British Journal
of Pharmacology (2006), 147(Suppl. 1), S277-S286.
©1
Homework Questions:
1. Briefly describe the differences between the sympathetic and
parasympathetic divisions of the autonomic nervous system,
including the neurotransmitter used at the respective
neuromuscular junctions.
2. Cholinergic receptors are divided into nicotinic and
muscarinic classes. How are these receptors different? Draw
the structures of nicotine and muscarine and show how they
might resemble the natural agonist, acetylcholine.
3. Methacholine, carbachol, and bethanechol are acetylcholine
agonists at the muscarinic receptor. Draw the structure of
each and explain the rationale behind the structural
modifications. Describe how each agonist is used clinically.
4. Atropine and scopolamine (hyocine) are cholinergic
antagonists at the muscarinic receptors. Draw their
structures, illustrate the structural resemblance to
acetylcholine, and describe their clinical utility.
©1
5. Describe the difference between a nondepolarising blocking
drug and a depolarizing blocking drug. Provide an example
of each.
6. Describe the ‘safe’ technique of ‘balanced anesthesia’.
7. What is the depolarizing drug, suxamethonium, used for?
Why is its utility limited?
8. Why are atracurium (and its single stereoisomer, cisatracurium) valuable as neuromuscular blocking agents
during surgery? Draw its structure. What structural feature
is important to limiting their half life in vivo?
©1