patrick an introduction to medicinal chemistry 3/e chapter 19 cholinergics, anticholinergics
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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 - PowerPoint PPT PresentationTRANSCRIPT
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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal
ChemistryChemistry 3/e 3/e
Chapter 19Chapter 19
CHOLINERGICS, CHOLINERGICS, ANTICHOLINERGICSANTICHOLINERGICS
& ANTICHOLINESTERASES& ANTICHOLINESTERASESPart 1: Cholinergics & anticholinesterasesPart 1: Cholinergics & anticholinesterases
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ContentsContents
Part 1: Cholinergics & anticholinesterases
1. Nerve Transmission (3 slides)2. Neurotransmitter3. 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 agonist5.2. Nicotine and muscarine as cholinergic agonists5.3. 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]
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CHOLINERGICCHOLINERGICNERVOUSNERVOUSSYSTEMSYSTEM
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1. Nerve Transmission1. Nerve TransmissionPeripheral nervous systemPeripheral nervous system
Peripheral nerves
Muscle
Gastro-intestinal tract (GIT)
Brain
Spinal cord
CNS
Heart
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1. Nerve Transmission1. Nerve TransmissionPeripheral nervous systemPeripheral nervous system
CNS(Somatic)
CNS(Autonomic)
Sympathetic
Parasympathetic
NA
Ach(N)
Synapse
Ach (N)
Ach(N)
Ach(N)
Ach(M)
Adrenalmedulla
Adrenaline
Skeletalmuscle
Synapse
AUTONOMIC
Smooth muscleCardiac muscle
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NerveNerve
1. Nerve Transmission1. Nerve TransmissionSynapsesSynapses
100-500AReceptorsReceptors
Release ofneurotransmitters
Receptor binding and new signal
Nerve impulseNerve impulse New signalNew signal
Vesicles containingneurotransmitters
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2. Neurotransmitter2. Neurotransmitter
Acetylcholine (Ach)Acetylcholine (Ach)
CholineCholineAcetylAcetyl
H3C OC NMe 3
O+
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3. Transmission process3. Transmission process
Signal in nerve 1Signal in nerve 1
Acetylcholinesterase enzymeAcetylcholinesterase enzyme
Cholinergic receptorCholinergic receptor. AcetylcholineAcetylcholine
VesicleVesicle
......
...
Nerve 1Nerve 1Nerve 2Nerve 2
SignalSignal
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3. Transmission process3. Transmission process
Vesicles fuse with membrane and release AchVesicles fuse with membrane and release Ach
Nerve 1Nerve 1Nerve 2Nerve 2
SignalSignal
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3. Transmission process3. Transmission process
Nerve 2Nerve 2
1©Nerve 2Nerve 2
3. Transmission process3. Transmission process
• Receptor binds AchReceptor binds Ach• Induced fit triggers 2Induced fit triggers 2oo message message• Triggers firing of nerve 2Triggers firing of nerve 2• Ach undergoes no reactionAch undergoes no reaction
22oo Message Message
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3. Transmission process3. Transmission process
• Ach departs receptorAch departs receptor• Receptor reverts to resting stateReceptor reverts to resting state• Ach binds to acetylcholinesteraseAch binds to acetylcholinesterase
Nerve 2Nerve 2
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3. Transmission process3. Transmission process
Ach hydrolysedAch hydrolysedby acetylcholinesteraseby acetylcholinesterase
Nerve 2Nerve 2Acetylcholine
H3CC
O
O
Choline
+ NMe3
C
O
H3C OH
Acetic acid
NMe3HO
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3. Transmission process3. Transmission process
Choline binds to carrier proteinCholine binds to carrier protein
Carrier protein for cholineCarrier protein for choline
Nerve 1Nerve 1Nerve 2Nerve 2
CholineCholine
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3. Transmission process3. Transmission process
Choline transported into nerveCholine transported into nerve
Nerve 1Nerve 1Nerve 2Nerve 2
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3. Transmission process3. Transmission process
Ach resynthesisedAch resynthesised
Nerve 1Nerve 1Nerve 2Nerve 2
E 1
Choline
+ CH2 NMe3CH2HOC
O
H3C SCoA
Acetylcholine
H3CC
O
ONMe3
E 1 = Choline acetyltransferase
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3. Transmission process3. Transmission process
Ach repackaged in vesiclesAch repackaged in vesicles
Nerve 1Nerve 1Nerve 2Nerve 2
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4. Cholinergic receptors4. Cholinergic receptors Receptor typesReceptor types• Not all cholinergic receptors are identicalNot all cholinergic receptors are identical• Two types of cholinergic receptor - nicotinic and muscarinicTwo types of cholinergic receptor - nicotinic and muscarinic• Named after natural products showing receptor selectivityNamed after natural products showing receptor selectivity
Acetylcholine is natural messenger for both receptor typesAcetylcholine is natural messenger for both receptor types
Activates cholinergic Activates cholinergic receptors at nerve synapsesreceptors at nerve synapsesand on skeletal muscleand on skeletal muscle
Activates cholinergic Activates cholinergic receptors on smoothreceptors on smoothmuscle and cardiac musclemuscle and cardiac muscle
NicotineNicotine
N
NMe
L-(+)-MuscarineL-(+)-Muscarine
OMe CH2NMe3
HO
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Peripheral nervous systemPeripheral nervous system
CNS(Somatic)
CNS(Autonomic)
Sympathetic
Parasympathetic
NA
Ach(N)
Synapse
Ach (N)
Ach(N)
Ach(N)
Ach(M)
Adrenalmedulla
Adrenaline
SkeletalMuscle
SOMATIC
Synapse
AUTONOMIC
Smooth MuscleCardiac Muscle
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Cellmembrane
Five glycoprotein subunitstraversing cell membrane
ReceptorBindingsite Messenger
Control of Cationic Ion Channel:Control of Cationic Ion Channel:
4.1 Nicotinic receptor4.1 Nicotinic receptor
Cellmembrane
Inducedfit
‘Gating’(ion channel opens)
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The binding sitesThe binding sites
Two ligand binding sitesTwo ligand binding sitesmainly on mainly on -subunits-subunits
Ion channelIon channel
xx subunits subunits
BindingBindingsitessites
4.1 Nicotinic receptor4.1 Nicotinic receptor
CellCellmembranemembrane
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Activation of a signal proteinActivation of a signal protein• Receptor binds messenger leading to an induced fitReceptor binds messenger leading to an induced fit• Opens a binding site for a signal protein (G-protein)Opens a binding site for a signal protein (G-protein)
closed
messenger
inducedfit
open
4.2 Muscarinic receptor - G Protein coupled receptor4.2 Muscarinic receptor - G Protein coupled receptor
G-proteinbound
G-proteinsplit
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Activation of membrane bound enzymeActivation of membrane bound enzyme• G-Protein is split and subunit activates a membrane bound G-Protein is split and subunit activates a membrane bound
enzymeenzyme• Subunit binds to an allosteric binding site on enzymeSubunit binds to an allosteric binding site on enzyme• Induced fit results in opening of an active siteInduced fit results in opening of an active site• Intracellular reaction is catalysedIntracellular reaction is catalysed
active site(closed)
active site(open)
Enzyme Enzyme
Intracellular reaction
4.2 Muscarinic receptor - G Protein coupled receptor4.2 Muscarinic receptor - G Protein coupled receptor
subunit
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5. Cholinergic agonists5. Cholinergic agonists
5.1 Acetylcholine as an agonist5.1 Acetylcholine as an agonist
AdvantagesAdvantages• Natural messengerNatural messenger• Easily synthesisedEasily synthesised
DisadvantagesDisadvantages• Easily hydrolysed in stomach (acid catalysed hydrolysis)Easily hydrolysed in stomach (acid catalysed hydrolysis)• Easily hydrolysed in blood (esterases)Easily hydrolysed in blood (esterases)• No selectivity between receptor typesNo selectivity between receptor types• No selectivity between different target organsNo selectivity between different target organs
Ac2ONMe3+
O HO NMe3 NMe3AcO
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5. Cholinergic agonists5. Cholinergic agonists
5.2 Nicotine and muscarine as cholinergic agonists5.2 Nicotine and muscarine as cholinergic agonists
AdvantagesAdvantages• More stable than AchMore stable than Ach• Selective for main cholinergic receptor typesSelective for main cholinergic receptor types• Selective for different organsSelective for different organs
DisadvantagesDisadvantages• Activate receptors for other chemical messengersActivate receptors for other chemical messengers• Side effects Side effects
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5. Cholinergic agonists5. Cholinergic agonists
5.3 Requirements for cholinergic agonists5.3 Requirements for cholinergic agonists
• Stability to stomach acids and esterasesStability to stomach acids and esterases• Selectivity for cholinergic receptorsSelectivity for cholinergic receptors• Selectivity between muscarinic and nicotinic receptorsSelectivity between muscarinic and nicotinic receptors
• Knowledge of binding siteKnowledge of binding site• SAR for acetylcholineSAR for acetylcholine
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AcetoxyAcetoxy
EthyleneEthylenebridgebridge
44 oo NitrogenNitrogen
Me ONMe3
O
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
NitrogenNitrogen
Me ONMe3
O
6. SAR for acetlcholine6. SAR for acetlcholine
Quaternary nitrogen is essentialQuaternary nitrogen is essential
Bad for activityBad for activity
OCMe3H3C
O
ONMe2H3C
O
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• Distance from quaternary nitrogen to ester is importantDistance from quaternary nitrogen to ester is important• Ethylene bridge must be retainedEthylene bridge must be retained
6. SAR for acetylcholine6. SAR for acetylcholine
Bad for activityBad for activity
O NMe3H3C
O
OH3C
O
NMe3
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
44 oo NitrogenNitrogen
Me ONMe3
O
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
NitrogenNitrogen
Me ONMe3
O
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Ester is importantEster is important
6. SAR for acetylcholine6. SAR for acetylcholine
Bad for activityBad for activity
ONMe3H3C
NMe3H3C
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
44 oo NitrogenNitrogen
Me ONMe3
O
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
NitrogenNitrogen
Me ONMe3
O
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Minimum of two methyl groups on quaternary nitrogen Minimum of two methyl groups on quaternary nitrogen
6. SAR for acetylcholine6. SAR for acetylcholine
Bad for activityBad for activity
ONH3C
O Et
Et
Et
ActiveActive
ON
H3C
O Et
Me
Me
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
44 oo NitrogenNitrogen
Me ONMe3
O
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
44 oo NitrogenNitrogen
Me ONMe3
O
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Methyl group of acetoxy group cannot be extended Methyl group of acetoxy group cannot be extended
6. SAR for acetylcholine6. SAR for acetylcholine
Bad for activityBad for activity
ONMe3
O
H3C
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
44 oo NitrogenNitrogen
Me ONMe3
O
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
NitrogenNitrogen
Me ONMe3
O
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Conclusions:Conclusions: • Tight fit between Ach and binding site Tight fit between Ach and binding site • Methyl groups fit into small hydrophobic pocketsMethyl groups fit into small hydrophobic pockets• Ester interacting by H-bondingEster interacting by H-bonding• Quaternary nitrogen interacting by ionic bondingQuaternary nitrogen interacting by ionic bonding
6. SAR for acetylcholine6. SAR for acetylcholine
AcetoxyAcetoxy
EthyleneEthylenebridgebridge
44 oo NitrogenNitrogen
Me ONMe3
O
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Trp-307Asp311
Trp-613Trp-616
Asn-617
O N
HH
CO2
7. Binding site (muscarinic)7. Binding site (muscarinic)
hydrophobic pocket
hydrophobic pocket
hydrophobic pockets
O O
CH3
N
CH3
CH3
CH3
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Trp-307Asp311
Trp-613Trp-616
Asn-617
O N
HH
CO2
7. Binding site (muscarinic)7. Binding site (muscarinic)
H-bonds
Ionic bond
vdw
vdw
vdwO O
CH3
N
CH3
CH3
CH3
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• Possible induced dipole dipole interaction between quaternary Possible induced dipole dipole interaction between quaternary nitrogen and hydrophobic aromatic rings in binding sitenitrogen and hydrophobic aromatic rings in binding site
• NN++ induces dipole in aromatic rings induces dipole in aromatic rings
7. Binding site (muscarinic)7. Binding site (muscarinic)
R
NMe3----
++++
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O
C
H
H
OMe
H
H
Me
N
Me
Me
• Several freely rotatable single bondsSeveral freely rotatable single bonds• Large number of possible conformationsLarge number of possible conformations• Active conformation does not necessarily equal the most Active conformation does not necessarily equal the most
stable conformationstable conformation
8. Active conformation of acetylcholine8. Active conformation of acetylcholine
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MUSCARINE
OMe CH2NMe3
HO
CH2NMe3Me
O
O
O
OMeNMe3
H
H
Rigid Analogues of acetylcholineRigid Analogues of acetylcholine
• Rotatable bonds ‘locked’ within ringRotatable bonds ‘locked’ within ring• Restricts number of possible conformationsRestricts number of possible conformations• Defines separation of ester and N Defines separation of ester and N
8. Active conformation of acetylcholine8. Active conformation of acetylcholine
Muscarinic receptor
ON
4.4A
Nicotinic receptor
ON
5.9A
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• Neighbouring group participationNeighbouring group participation• Increases electrophilicity of carbonyl groupIncreases electrophilicity of carbonyl group
• Increases sensitivity to nucleophilesIncreases sensitivity to nucleophiles
9. Instability of acetylcholine9. Instability of acetylcholine
O
CO
Me3N
H3C
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10. Design of cholinergic agonists10. Design of cholinergic agonists
RequirementsRequirements
• Correct sizeCorrect size
• Correct pharmacophore - ester and quaternary nitrogenCorrect pharmacophore - ester and quaternary nitrogen
• Increased stability to acid and esterasesIncreased stability to acid and esterases
• Increased selectivityIncreased selectivity
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Use of steric shieldsUse of steric shields
RationaleRationale
• Shields protect ester from nucleophiles and enzymesShields protect ester from nucleophiles and enzymes
• Shield size is importantShield size is important
• Must be large enough to hinder hydrolysisMust be large enough to hinder hydrolysis
• Must be small enough to fit binding siteMust be small enough to fit binding site
10. Design of cholinergic agonists10. Design of cholinergic agonists
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10. Design of cholinergic agonists10. Design of cholinergic agonists
MethacholineMethacholine
PropertiesProperties• Three times more stable than acetylcholineThree times more stable than acetylcholine• Increasing the shield size increases stability but decreases Increasing the shield size increases stability but decreases
activityactivity• Selective for muscarinic receptors over nicotinic receptorsSelective for muscarinic receptors over nicotinic receptors• SS-enantiomer is more active than the -enantiomer is more active than the RR-enantiomer-enantiomer• Stereochemistry matches muscarineStereochemistry matches muscarine• Not used clinicallyNot used clinically
asymmetric centre
hinders binding to esterasesand provides a shield to nucleophilic attack
MUSCARINE
OMe CH2NMe3
HO
HCH2NMe3Me
Me
O
O
(S) (R)Me
O
O
H
Me CH2NMe3
Me ONMe3
O Me
*
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10. Design of cholinergic agonists10. Design of cholinergic agonists
Use of electronic factorsUse of electronic factors
• Replace ester with urethaneReplace ester with urethane• Stabilises the carbonyl groupStabilises the carbonyl group
H2NC
O
C
O
H2N
H2NC
O
=
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10. Design of cholinergic agonists10. Design of cholinergic agonists
PropertiesProperties• Resistant to hydrolysisResistant to hydrolysis• Long lastingLong lasting• NHNH22 and CH and CH33 are equal sizes. Both fit the hydrophobic pocket are equal sizes. Both fit the hydrophobic pocket• NHNH22 = bio-isostere = bio-isostere • Muscarinic activity = nicotinic activityMuscarinic activity = nicotinic activity• Used topically for glaucomaUsed topically for glaucoma
CarbacholCarbacholOC
O
H2NNMe3
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10. Design of cholinergic agonists10. Design of cholinergic agonists
Steric + Electronic factorsSteric + Electronic factors
PropertiesProperties• Very stableVery stable• Orally activeOrally active• Selective for the muscarinic receptorSelective for the muscarinic receptor
• Used to stimulate GI tract and urinary bladder after surgeryUsed to stimulate GI tract and urinary bladder after surgery
BethanecholBethanechol*H2N
C
O
ONMe3
Me
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10. Design of cholinergic agonists10. Design of cholinergic agonists
Nicotinic selective agonistNicotinic selective agonist
MeC
O
O * asymmetric centreNMe3
Me
*
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11. Uses of cholinergic agonists11. Uses of cholinergic agonists
Nicotinic selective agonistsNicotinic selective agonists
Treatment of myasthenia gravis Treatment of myasthenia gravis
- lack of acetylcholine at skeletal muscle causing weakness- lack of acetylcholine at skeletal muscle causing weakness
Muscarinic selective agonistsMuscarinic selective agonists• Treatment of glaucomaTreatment of glaucoma• Switching on GIT and urinary tract after surgerySwitching on GIT and urinary tract after surgery• Treatment of certain heart defects. Decreases heart muscle Treatment of certain heart defects. Decreases heart muscle
activity and decreases heart rateactivity and decreases heart rate
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Peripheral nervous systemPeripheral nervous system
CNS(Somatic)
CNS(Autonomic)
Sympathetic
Parasympathetic
NA
Ach(N)
Synapse
Ach (N)
Ach(N)
Ach(N)
Ach(M)
Adrenalmedulla
Adrenaline
SkeletalMuscle
SOMATIC
Synapse
AUTONOMIC
Smooth MuscleCardiac Muscle