Drugs acting on parasympathetic nervous system2

CHOLINERGICS, ANTICHOLINERGICS
& ANTICHOLINESTERASES
Part 2: Cholinergics & anticholinesterases
Mr. Somdatta Y Chaudhari
Dept. of Pharm. Chemistry
P.E.S. Modern College of Pharmacy, Nigdi
P.E.S. Modern College of Pharmacy, Nigdi 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)

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
Ach
Antagonist
Ach
Postsynaptic
nerve
Ach

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

12.1 Atropine
• 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
*
N
H
O
C
O
Me
CH
CH2OH
easily racemised

• 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
(such as a nerve gas).P.E.S. Modern College of Pharmacy, Nigdi 6

• 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.

12.2 Hyoscine (scopolamine)
• Source - thorn apple
• Medical use - treatment of motion sickness
• Used as a truth drug (CNS effects)
*
N
H
O
C
O
Me
CH
CH2OHO
H
H

Hyoscine (Scopolamine)

12.3 Comparison of atropine with acetylcholine
• 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
N
O
C
O
Me
H
CH
CH2OH
C
O
O CH3
NMe3
CH2CH2

12.4 Analogues of atropine
• Analogues are fully ionised
• Analogues unable to cross the blood brain barrier
• No CNS side effects
Atropine methonitrate
(lowers GIT motility)
N
H
O
C
O
CH3
CH
CH2OH
H3C
NO3
Ipratropium
(bronchodilator & anti-asthmatic)
N
H
O
C
O
CH(CH3)2
CH
CH2OH
H3C
Br

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

12.5 Simplified Analogues
Pharmacophore = ester + basic amine + aromatic ring
Amprotropine
N
CH2
CH2
CH2
O
C
O
Et
CH
CH2OH
Et
Tridihexethyl bromide
HO C CH2CH2N(Et)3 Br
Propantheline chloride
Cl
O C
O
O CH2CH2 N
CH
Me
CH
Me Me
Me
Me

12.5 Simplified Analogues
Tropicamide
(opthalmics)
Cyclopentolate
(opthalmics)
Benztropine
(Parkinsons disease)
Benzhexol
(Parkinsons disease)
Pirenzepine
(anti-ulcer)
CH
CH2OH
O
N
CH2CH3
N
N
H
O
CH
Me
N
CH
N N
CHN
C O
CH2
N
N
O
Me
CH
O
O
OH
Me2N

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 P.E.S. Modern College of Pharmacy, Nigdi 15

12.6 SAR for Antagonists
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
R2N
CH2
CH2
O
C
O
CH
R'
R'
R' = Aromatic or
Heteroaromatic

InactiveActive
Cl
O C
O
O CH2CH2 N
CH
Me
CH
Me Me
Me
Me CH2
C
O
O CH2CH2NR2
12.6 SAR for Antagonists

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
SAR for Antagonists SAR for Agonists
12.6 SAR for Antagonists vs. Agonists

RECEPTOR SURFACE
Acetylcholine
binding site
12.7 Binding Site for Antagonists
van der Waals
binding regions
for antagonists

12.7 Binding Site for Antagonists
CH
Me
Me
CH
MeMe
N
Me
CH2CH2O
C
O
O
Cl
H2N Asn
CO2
CH2
CH2
O
O
C
NMeR2
O

13.1 Curare
• Extract from ourari plant
• Used for poison arrows
• Causes paralysis (blocks acetylcholine signals to muscles)
• Active principle = tubocurarine
Tubocurarine
N
HO
MeO
O
CH2
OMe
N
Me
Me
H
O
Me
CH2
OH
H
H

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.

• 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.

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

13.2 Binding
a) Receptor dimer
S
b) Interaction with tubocurarine
protein complex
(5 subunits)
diameter=8nm
8nm
9-10nm
N N
N N Tubocurarine
Acetylcholine binding site

13.3 Analogues of tubocurarine
• Long lasting
• Long recovery times
• Side effects on heart
• No longer in clinical use
Decamethonium
Me3N(CH2)10NMe3

Suxamethonium
(Succinylcholine)
Me3NCH2CH2 O
C
O
CH2
C
O
O CH2CH2NMe3CH2
• Esters incorporated
• Shorter lifetime (5 min)
• Fast onset and short duration
• Frequently used during intubation
• Side effects at autonomic ganglia

• 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
Pancuronium (R=Me)
Vecuronium (R=H)
Me
O
NMe
N
O
Me
Me
Me
O
O
H
H H
H

• 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
administered P.E.S. Modern College of Pharmacy, Nigdi 29

• 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
Atracurium
N
CH2 CH2
C
O
O
MeO
OMe
H
N
(CH2)5MeO O
C
OMe
O
CH2 CH2
Me
MeO
OMe
OMe
OMe

Atracurium stable at acid pH
Hofmann elimination at blood pH (7.4)
N
Me
CH2
Ph
CH C
H
O
R
ACTIVE
-H
CHH2C C
O
Ph
R
N
Me
INACTIVE

• 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.

Mivacurium
• Faster onset (2 min)
• Shorter duration (15 min)
N
MeO
OMe
H3C
NMeO
OMe
Me
MeO
OMe
OMe
OMe
O
O
O
O

• The use of mivacurium has declined in recent years, in
favor of other agents with better overall profile.

Drugs acting on parasympathetic nervous system2

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