patrick an introduction to medicinal chemistry 3/e chapter 19 cholinergics, anticholinergics

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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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Vesicles fuse with membrane and release AchVesicles fuse with membrane and release Ach


SignalSignal

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Nerve 2Nerve 2

1©Nerve 2Nerve 2


• 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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• 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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Ach hydrolysedAch hydrolysedby acetylcholinesteraseby acetylcholinesterase

Nerve 2Nerve 2Acetylcholine

H3CC

O

O

Choline

+ NMe3

C

O

H3C OH

Acetic acid

NMe3HO

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Choline binds to carrier proteinCholine binds to carrier protein

Carrier protein for cholineCarrier protein for choline


CholineCholine

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Choline transported into nerveCholine transported into nerve


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Ach resynthesisedAch resynthesised


E 1

Choline

+ CH2 NMe3CH2HOC

O

H3C SCoA

Acetylcholine

H3CC

O

ONMe3

E 1 = Choline acetyltransferase

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Ach repackaged in vesiclesAch repackaged in vesicles


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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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5.2 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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5.3 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


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


O NMe3H3C

O

OH3C

O

NMe3

AcetoxyAcetoxy



Me ONMe3

O

AcetoxyAcetoxy


NitrogenNitrogen

Me ONMe3

O

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Ester is importantEster is important



ONMe3H3C

NMe3H3C

AcetoxyAcetoxy



Me ONMe3

O

AcetoxyAcetoxy


NitrogenNitrogen

Me ONMe3

O

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Minimum of two methyl groups on quaternary nitrogen Minimum of two methyl groups on quaternary nitrogen



ONH3C

O Et

Et

Et

ActiveActive

ON

H3C

O Et

Me

Me

AcetoxyAcetoxy



Me ONMe3

O

AcetoxyAcetoxy



Me ONMe3

O

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Methyl group of acetoxy group cannot be extended Methyl group of acetoxy group cannot be extended



ONMe3

O

H3C

AcetoxyAcetoxy



Me ONMe3

O

AcetoxyAcetoxy


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


AcetoxyAcetoxy



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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• 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


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


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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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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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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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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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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

patrick an introduction to medicinal chemistry 3/e chapter 19 cholinergics, anticholinergics

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