Transcript 12. Cholinergic Antagonists (Muscarinic receptor)

Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 19
CHOLINERGICS, ANTICHOLINERGICS
& ANTICHOLINESTERASES
Part 2: Cholinergics & anticholinesterases
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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]
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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
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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
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http://www.fairview.org/healthlibrary/content/ma_atrosulf_ma.htm
http://www.medicinenet.com/atropine-oral/article.htm
http://healthresources.caremark.com/topic/parkinsondrugs
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Cycloplegia
Cycloplegia is the paralysis of the ciliary muscle, resulting in a loss of accommodation.
Cycloplegic drugs, including atropine, cyclopentolate, succinylcholine, homatropine, scopolamine and
tropicamide, are indicated for use in cycloplegic refractions and the treatment of uveitis. Other cycloplegic
drugs include Neostigmine, Phentolamine and Pilocarpine
mydriasis
Mydriasis
Classifications and external resources
An abnormally dilated pupil.
Mydriasis is an excessive dilation of the pupil due to disease or drugs. Although the pupil will normally dilate in
the dark, it is usually quite constricted in the light. A mydriatic pupil will remain excessively large, even in a
bright environment.
Constriction of the pupil is called miosis
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12. Cholinergic Antagonists (Muscarinic receptor)
Me
12.1 Atropine
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
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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)
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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
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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
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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
Diphenoxylate is an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal
contractions. It was discovered at Janssen Pharmaceutica in 1956. It is a congener to the narcotic Meperidine of
which the common brand name is Demerol. This being the case, this medication is potentially habit-forming,
particularly in high doses or when long-time usage is involved. Because of this, diphenoxylate is manufactured and
marketed as a combination drug with atropine (Lomotil®).
This pharmaceutical strategy is designed to discourage abuse, because the anticholinergic effect of atropine will
produce severe weakness and nausea if standard dosage is exceeded.
This medication is classified as a Schedule V under the Controlled Substances Act by the Food and Drug
Administration (FDA) and the DEA in the United States when used in preparations. When diphenoxylate is used
alone, it is classified as a Schedule II.
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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
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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)
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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
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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
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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
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12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists
van der Waals
binding regions
for antagonists
Acetylcholine
binding site
RECEPTOR SURFACE
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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
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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
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Tubocurarine chloride is a competitive antagonist of nicotinic neuromuscular
acetylcholine receptors, used to paralyse patients undergoing anaesthesia. 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.
The correct chemical structure was only elucidated circa 1970, even though the
plant had been known since the Spanish Conquest.
The word curare comes from the South American Indian name for the arrow
poison: "ourare". Presumably the initial syllable was pronounced with a heavy
glottal stroke. Tubocurarine is so called because the plant samples containing it
were first shipped to Europe in tubes.
Today, tubocurarine has fallen into disuse in western medicine, as safer synthetic
alternatives such as atracurium are available. However, tubocurarine is still used in
the United States and elsewhere as part of the lethal injection procedure.
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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
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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
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13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Me3N(CH2) 10NMe3
Me3NCH2CH2
O
Decamethonium
•
•
•
Long lasting
Long recovery times
Side effects on heart
O
O
C
C
CH2 CH2
O
CH2 CH2NMe3
Suxamethonium
•
•
•
•
Esters incorporated
Shorter lifetime (5 min)
Fast onset and short duration
Side effects at autonomic ganglia
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Suxamethonium chloride
From Wikipedia, the free encyclopedia
(Redirected from Succinylcholine)
Routes
Intravenous
Suxamethonium chloride (also known as succinylcholine, scoline, or SUX) is a white crystalline
substance, it is odourless and highly soluble in water. The compound consists of two acetylcholine
molecules that are linked by their acetyl groups. Suxamethonium is sold under several trademark names
such as Anectine®, and may be referred to as "sux" for short.
Suxamethonium acts as a depolarizing muscle relaxant. It imitates the action of acetylcholine at the
neuromuscular junction, but it is not degraded by acetylcholinesterase but by pseudocholinesterase, a
plasma cholinesterase. This hydrolysis by pseudocholinesterase is much slower than that of
acetylcholine by acetylcholinesterase.lcholinesterase.
There are two phases to the blocking effect of suxamethonium. The first is due to the prolonged
stimulation of the acetylcholine receptor results first in disorganized muscle contractions (fasciculations,
considered to be a side effect as mentioned below), as the acetylcholine receptors are stimulated. On
stimulation, the acetylcholine receptor becomes a general ion channel, so there is a high flux of
potassium out of the cell, and of sodium into the cell, resulting in an endplate potential less than the
action potential. So, after the initial firing, the cell remains refractory.
i
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Suxamethonium chloride
On continued stimulation, the acetylcholine receptors become desensitised and close. This means that new
acetylcholine signals do not cause an action potential; and the continued binding of suxamethonium is ignored. This
is the principal anaesthetic effect of suxamethonium, and wears off as the suxamethonium is degraded, and the
acetylcholine receptors return to their normal configuration. The side effect of hyperkalaemia is because the
acetylcholine receptor is propped open, allowing continued flow of potassium ions into the extracellular fluid. A typical
increase of potassium ion serum concentration on administration of suxamethonium is 0.5 mmol per litre, whereas
the normal range of potassium is 3.5 to 5 mmol per litre: a significant increase which results in the other side-effects
of ventricular fibrillation due to reduced to action potential initiation in the heart.
Its medical uses are limited to short-term muscle relaxation in anesthesia and intensive care, usually for
facilitation of endotracheal intubation. Despite its many undesired effects on the circulatory system and skeletal
muscles (including malignant hyperthermia, a rare but life-threatening disease), it is perennially popular in
emergency medicine because it arguably has the fastest onset and shortest duration of action of all muscle
relaxants. Both are major points of consideration in the context of trauma care, where paralysis must be induced
very quickly and the use of a longer-acting agent might mask the presence of a neurological deficit.
A single intravenous dose of 1.0 to 1.5 milligrams per kilogram of body weight for adults or 2.0 milligrams per
kilogram for pediatrics will cause flaccid paralysis within a minute of injection. For intramuscular injection higher
doses are used and the effects last somewhat longer. Suxamethonium is quickly degraded by plasma
cholinesterase and the duration of effect is usually in the range of a few minutes. When plasma levels of
cholinesterase are greatly diminished or an atypical form of cholinesterase is present (an otherwise harmless
inherited disorder), paralysis may last much longer.
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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
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
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Atracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the
category of non-depolarising neuromuscular blocking agents, used adjunctively in
anaesthesia to facilitate endotracheal intubation and to provide skeletal muscle
relaxation during surgery or mechanical ventilation.
Side effects owing to histamine liberation are rash, reflex increase in heart rate, low
blood pressure and bronchospasm.
It is a bisbenzyltetrahydroisoquinolinium mixture of 10 Stereoisomers. Atracurium was
first synthesized, in 1974 by George H. Dewar, in John B. Stenlake's medicinal
chemistry research group at Strathclyde University, Scotland. It is the first nondepolarising non-steroidal skeletal muscle relaxant rationally designed to undergo
chemodegradation in vivo. Atracurium was licensed to Burroughs Wellcome Co., which
developed atracurium and eventually marketed it (as a mixture of all ten
stereoisomers)under the name Tracrium. Atracurium's rate of degradation in vivo is
influenced by pH and temperature.
Atracurium was succeeded by cisatracurium, which is the R-cis R-cis isomer
constituent of atracurium. The pharamcodynamic and adverse effect profile of
cisatracurium proved to be superior to that of atracurium. Cisatracurium was made
available worldwide as Nimbex, with its clinical development solely undertaken by
Burroughs Wellcome Co.
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Atracurium is classified as an intermediate-acting neuromuscular blocking©agent.
Atracurium
Pharmacokinetic data
Bioavailability
100% (IV)
Protein binding
82%
MetabolismHoffman elimination (retro-Michael addition) and ester hydrolysis
Half life
17-21 minutes
Excretion ?
Routes
IV
Atracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarising
neuromuscular blocking agents, used adjunctively in anaesthesia to facilitate endotracheal intubation and to
provide skeletal muscle relaxation during surgery or mechanical ventilation.
Side effects owing to histamine liberation are rash, reflex increase in heart rate, low blood pressure and
bronchospasm.
It is a bisbenzyltetrahydroisoquinolinium mixture of 10 Stereoisomers. Atracurium was first synthesized, in
1974 by George H. Dewar, in John B. Stenlake's medicinal chemistry research group at Strathclyde
University, Scotland. It is the first non-depolarising non-steroidal skeletal muscle relaxant rationally designed
to undergo chemodegradation in vivo. Atracurium was licensed to Burroughs Wellcome Co., which developed
atracurium and eventually marketed it (as a mixture of all ten stereoisomers)under the name Tracrium.
Atracurium's rate of degradation in vivo is influenced by pH and temperature.
Atracurium was succeeded by cisatracurium, which is the R-cis R-cis isomer constituent of atracurium. The
pharamcodynamic and adverse effect profile of cisatracurium proved to be superior to that of atracurium.
Cisatracurium was made available worldwide as Nimbex, with its clinical development solely undertaken by
Burroughs Wellcome Co.
Atracurium is classified as an intermediate-acting neuromuscular blocking age
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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)
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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)
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