Transcript No Slide Title

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)
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
©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
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
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
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
C
Me
CH
O
Me
Me
O
H 2N
CH2
Cl
CH2
NMeR2
CO2
©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
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
Me 3N(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
©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
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
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