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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 19 CHOLINERGICS, ANTICHOLINERGICS & ANTICHOLINESTERASES Part 1: Cholinergics & anticholinesterases. Contents Part 1: Cholinergics & anticholinesterases 1. Nerve Transmission (3 slides) 2. Neurotransmitter

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Presentation Transcript
slide1

Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 19

CHOLINERGICS, ANTICHOLINERGICS

& ANTICHOLINESTERASES

Part 1: Cholinergics & anticholinesterases

slide2

Contents

Part 1: Cholinergics & anticholinesterases

1. Nerve Transmission (3 slides)

2. Neurotransmitter

3. Transmission process (10 slides)

4. Cholinergic receptors (2 slides)

4.1. Nicotinic receptor (2 slides)

4.2. Muscarinic receptor - G Protein coupled receptor (2 slides)

5. Cholinergic agonists

5.1. Acetylcholine as an agonist

5.2. Nicotine and muscarine as cholinergic agonists

5.3. Requirements for cholinergic agonists

6. SAR for acetlcholine (6 slides)

7. Binding site (muscarinic) (3 slides)

8. Active conformation of acetylcholine (2 slides)

9. Instability of acetylcholine

10. Design of cholinergic agonists (7 slides)

11. Uses of cholinergic agonists (2 slides)

[46 slides]

slide3

CHOLINERGIC

NERVOUS

SYSTEM

slide4

1. Nerve Transmission

Peripheral nervous system

CNS

Brain

Peripheral nerves

Muscle

Heart

Gastro-

intestinal

tract

(GIT)

Spinal cord

slide5

Sympathetic nervous system = ‘Fight or Flight Response’

Parasympathetic nervous system = ‘Rest and Digest Response’

Link

Link

slide6

Skeletal

muscle

CNS

(Somatic)

CNS

(Autonomic)

Synapse

Sympathetic

Adrenaline

Adrenal

medulla

AUTONOMIC

Parasympathetic

Smooth muscle

Cardiac muscle

1. Nerve Transmission

Peripheral nervous system

Ach

(N)

Ach (N)

NA

Ach

(N)

Synapse

Ach

(M)

Ach

(N)

slide10

100-500A

Receptors

New signal

Nerve impulse

Nerve

Nerve

Vesicles containing

neurotransmitters

1. Nerve Transmission

Synapses

Release of

neurotransmitters

Receptor binding

and new signal

slide11

O

+

C

N

M

e

3

H

C

O

3

Acetyl

Choline

2. Neurotransmitter

Acetylcholine (Ach)

slide12

.

.

.

.

.

.

Nerve 2

.

.

.

Nerve 1

Signal

.

Acetylcholinesterase enzyme

Acetylcholine

Cholinergic receptor

Vesicle

3. Transmission process

Signal in nerve 1

slide13

Nerve 2

Nerve 1

Signal

3. Transmission process

Vesicles fuse with membrane and release Ach

slide14

Nerve 2

3. Transmission process

slide15

2o Message

Nerve 2

3. Transmission process

  • Receptor binds Ach
  • Induced fit triggers 2o message
  • Triggers firing of nerve 2
  • Ach undergoes no reaction
slide16

Nerve 2

3. Transmission process

  • Ach departs receptor
  • Receptor reverts to resting state
  • Ach binds to acetylcholinesterase
slide17

Nerve 2

3. Transmission process

Ach hydrolysed

by acetylcholinesterase

slide18

Choline

Nerve 2

Nerve 1

Carrier protein for choline

3. Transmission process

Choline binds to carrier protein

slide19

Nerve 2

Nerve 1

3. Transmission process

Choline transported into nerve

slide20

Nerve 2

Nerve 1

E 1 = Choline acetyltransferase

3. Transmission process

Ach resynthesised

slide21

Nerve 2

Nerve 1

3. Transmission process

Ach repackaged in vesicles

slide22

Nicotine

L-(+)-Muscarine

4. Cholinergic receptors

  • Receptor types
  • Not all cholinergic receptors are identical
  • Two types of cholinergic receptor - nicotinic and muscarinic
  • Named after natural products showing receptor selectivity

Activates cholinergic

receptors at nerve synapses

and on skeletal muscle

Activates cholinergic

receptors on smooth

muscle and cardiac muscle

Acetylcholine is natural messenger for both receptor types

slide23

Nicotine comprises up the 3% the dry weight of the tobacco leaf

  • When inhaled, it rapidly crosses the blood-brain barrier where it activates (acts as an agonist at) the acetylcholine receptors
  • Addiction to nicotine is reported to be one of the hardest addictions to break.
slide24

Muscarine is the active poisonous ingredient in several species of mushrooms

  • Ingestion causes severe nausea and diarrhea as the muscarine acts as an acetylcholine agonist. Also causes perspiration and lacrimation (tearing).
  • The antidote is atropine, an acetycholine antagonist at the muscarinic receptor.
slide25

Skeletal

Muscle

CNS

(Somatic)

SOMATIC

CNS

(Autonomic)

Synapse

Sympathetic

Adrenaline

Adrenal

medulla

AUTONOMIC

Parasympathetic

Smooth Muscle

Cardiac Muscle

Peripheral nervous system

Ach

(N)

Ach (N)

NA

Ach

(N)

Synapse

Ach

(M)

Ach

(N)

slide26

Binding

site

Receptor

Messenger

Cell

membrane

Cell

Induced

fit

‘Gating’

(ion channel

opens)

membrane

Five glycoprotein subunits

traversing cell membrane

4.1 Nicotinic receptor

Control of Cationic Ion Channel:

slide27

a

g

Binding

sites

a

b

d

Ion channel

a

b

g

d

a

Cell

membrane

Two ligand binding sites

mainly on a-subunits

4.1 Nicotinic receptor

The binding sites

2xa, b, g, d subunits

slide28

messenger

induced

fit

closed

open

G-protein

bound

G-protein

split

4.2 Muscarinic receptor - G Protein coupled receptor

  • Activation of a signal protein
  • Receptor binds messenger leading to an induced fit
  • Opens a binding site for a signal protein (G-protein)
slide29

Enzyme

Enzyme

subunit

4.2 Muscarinic receptor - G Protein coupled receptor

  • Activation of membrane bound enzyme
  • G-Protein is split and subunit activates a membrane bound enzyme
  • Subunit binds to an allosteric binding site on enzyme
  • Induced fit results in opening of an active site
  • Intracellular reaction is catalysed

active site

(open)

active site

(closed)

Intracellular

reaction

slide30

5. Cholinergic agonists

5.1 Acetylcholine as an agonist

  • Advantages
  • Natural messenger
  • Easily synthesised
  • Disadvantages
  • Easily hydrolysed in stomach (acid catalysed hydrolysis)
  • Easily hydrolysed in blood (esterases)
  • No selectivity between receptor types
  • No selectivity between different target organs
slide31

5. Cholinergic agonists

5.2 Nicotine and muscarine as cholinergic agonists

  • Advantages
  • More stable than Ach
  • Selective for main cholinergic receptor types
  • Selective for different organs
  • Disadvantages
  • Activate receptors for other chemical messengers
  • Side effects
slide32

5. Cholinergic agonists

5.3 Requirements for cholinergic agonists

  • Stability to stomach acids and esterases
  • Selectivity for cholinergic receptors
  • Selectivity between muscarinic and nicotinic receptors
  • Knowledge of binding site
  • SAR for acetylcholine
slide33

Ethylene

bridge

Ethylene

bridge

o

Acetoxy

4

Nitrogen

Acetoxy

Nitrogen

Bad for activity

6. SAR for acetlcholine

Quaternary nitrogen is essential

slide34

Ethylene

bridge

Ethylene

bridge

o

Acetoxy

4

Nitrogen

Acetoxy

Nitrogen

Bad for activity

6. SAR for acetylcholine

  • Distance from quaternary nitrogen to ester is important
  • Ethylene bridge must be retained
slide35

Ethylene

bridge

Ethylene

bridge

o

Acetoxy

4

Nitrogen

Acetoxy

Nitrogen

Bad for activity

6. SAR for acetylcholine

Ester is important

slide36

Ethylene

bridge

Ethylene

bridge

o

Acetoxy

4

Nitrogen

o

Acetoxy

4

Nitrogen

Bad for activity

Active

6. SAR for acetylcholine

Minimum of two methyl groups on quaternary nitrogen

slide37

Ethylene

bridge

Ethylene

bridge

o

Acetoxy

4

Nitrogen

Acetoxy

Nitrogen

Bad for activity

6. SAR for acetylcholine

Methyl group of acetoxy group cannot be extended

slide38

Ethylene

bridge

o

Acetoxy

4

Nitrogen

6. SAR for acetylcholine

  • Conclusions:
  • Tight fit between Ach and binding site
  • Methyl groups fit into small hydrophobic pockets
  • Ester interacting by H-bonding
  • Quaternary nitrogen interacting by ionic bonding
slide39

hydrophobic

pocket

Trp-307

Asp311

hydrophobic

pockets

Trp-616

Trp-613

hydrophobic

pocket

Asn-617

7. Binding site (muscarinic)

slide40

vdw

Trp-307

Asp311

vdw

vdw

Trp-616

Trp-613

Asn-617

7. Binding site (muscarinic)

Ionic bond

H-bonds

slide41

d +

d +

d -

d -

7. Binding site (muscarinic)

  • Possible induced dipole dipole interaction between quaternary nitrogen and hydrophobic aromatic rings in binding site
  • N+ induces dipole in aromatic rings
slide42

8. Active conformation of acetylcholine

  • Several freely rotatable single bonds
  • Large number of possible conformations
  • Active conformation does not necessarily equal the most stable conformation
slide43

Muscarinic

receptor

Nicotinic

receptor

8. Active conformation of acetylcholine

Rigid Analogues of acetylcholine

  • Rotatable bonds ‘locked’ within ring
  • Restricts number of possible conformations
  • Defines separation of ester and N
slide44

9. Instability of acetylcholine

  • Neighbouring group participation
  • Increases electrophilicity of carbonyl group
  • Increases sensitivity to nucleophiles
slide45

10. Design of cholinergic agonists

  • Requirements
  • Correct size
  • Correct pharmacophore - ester and quaternary nitrogen
  • Increased stability to acid and esterases
  • Increased selectivity
slide46

10. Design of cholinergic agonists

Use of steric shields

  • Rationale
  • Shields protect ester from nucleophiles and enzymes
  • Shield size is important
  • Must be large enough to hinder hydrolysis
  • Must be small enough to fit binding site
slide47

hinders binding to esterases

and provides a shield to

nucleophilic attack

asymmetric centre

10. Design of cholinergic agonists

Methacholine

  • Properties
  • Three times more stable than acetylcholine
  • Increasing the shield size increases stability but decreases
  • activity
  • Selective for muscarinic receptors over nicotinic receptors
  • S-enantiomer is more active than the R-enantiomer
  • Stereochemistry matches muscarine
  • Not used clinically
slide48

The primary clinical use of methacholine is as an acetylcholine agonist at the muscarinic receptor

  • As such, it is utilized in a test for asthma, called the ‘bronchial challenge test’
  • The methacholine provokes bronchoconstriction
  • Asthmatic patients, which already have airway hyperactivity, are more sensitive to the effect of methacholine, and this reaction can be quantified using a breathing test called spirometry..
slide49

=

10. Design of cholinergic agonists

  • Use of electronic factors
  • Replace ester with urethane
  • Stabilises the carbonyl group
slide50

Carbachol

10. Design of cholinergic agonists

  • Properties
  • Resistant to hydrolysis
  • Long lasting
  • NH2 and CH3 are equal sizes. Both fit the hydrophobic pocket
  • NH2 = bio-isostere
  • Muscarinic activity = nicotinic activity
  • Used topically for glaucoma
slide51

Glaucoma is an eye disease, characterized by increased intraocular pressure. It leads to irreversible loss of vision and is the second leading cause of blindness.

  • Treatments for glaucoma focus on relieving the pressure.
  • Carbachol causes miosis (constriction of the pupil), by contracting the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humour
slide52

Bethanechol

10. Design of cholinergic agonists

Steric + Electronic factors

  • Properties
  • Very stable
  • Orally active
  • Selective for the muscarinic receptor
  • Used to stimulate GI tract and urinary bladder after surgery
slide54

10. Design of cholinergic agonists

Nicotinic selective agonist

slide55

11. Uses of cholinergic agonists

  • Nicotinic selective agonists
  • Treatment of myasthenia gravis
  • - lack of acetylcholine at skeletal muscle causing weakness
  • Muscarinic selective agonists
  • Treatment of glaucoma
  • Switching on GIT and urinary tract after surgery
  • Treatment of certain heart defects. Decreases heart muscle activity and decreases heart rate
slide56

Skeletal

Muscle

CNS

(Somatic)

SOMATIC

CNS

(Autonomic)

Synapse

Sympathetic

Adrenaline

Adrenal

medulla

AUTONOMIC

Parasympathetic

Smooth Muscle

Cardiac Muscle

Peripheral nervous system

Ach

(N)

Ach (N)

NA

Ach

(N)

Synapse

Ach

(M)

Ach

(N)