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Tags : Neurology, Cholinergics, anticholinesterases, Nerve Transmission, Neurotransmitter

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Slide 1-

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 19 CHOLINERGICS, ANTICHOLINERGICS & ANTICHOLINESTERASES Part 1: Cholinergics & anticholinesterases
Slide 2-

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]
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CHOLINERGIC NERVOUS SYSTEM
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1. Nerve Transmission Peripheral nervous system Peripheral nerves Muscle Gastro- intestinal tract (GIT) Brain Spinal cord CNS Heart
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1. Nerve Transmission Peripheral nervous system CNS (Somatic) CNS (Autonomic) Sympathetic Parasympathetic NA Ach (N) Synapse Ach (N) Ach (N) Ach (N) Ach (M) Adrenal medulla Adrenaline Skeletal muscle Synapse AUTONOMIC Smooth muscle Cardiac muscle
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Nerve Nerve 1. Nerve Transmission Synapses 100-500A Receptors Release of neurotransmitters Receptor binding and new signal Nerve impulse New signal Vesicles containing neurotransmitters
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2. Neurotransmitter Acetylcholine (Ach) Choline Acetyl H 3 C O C N M e 3 O +
Slide 8-

3. Transmission process Signal in nerve 1 Acetylcholinesterase enzyme Cholinergic receptor . Acetylcholine Vesicle . . . . . . . . . Nerve 1 Nerve 2 Signal
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3. Transmission process Vesicles fuse with membrane and release Ach Nerve 1 Nerve 2 Signal
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3. Transmission process Nerve 2
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Nerve 2 3. Transmission process Receptor binds Ach Induced fit triggers 2o message Triggers firing of nerve 2 Ach undergoes no reaction 2o Message
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3. Transmission process Ach departs receptor Receptor reverts to resting state Ach binds to acetylcholinesterase Nerve 2
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3. Transmission process Ach hydrolysed by acetylcholinesterase Nerve 2
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3. Transmission process Choline binds to carrier protein Carrier protein for choline Nerve 1 Nerve 2 Choline
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3. Transmission process Choline transported into nerve Nerve 1 Nerve 2
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3. Transmission process Ach resynthesised Nerve 1 Nerve 2 E 1 = Choline acetyltransferase
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3. Transmission process Ach repackaged in vesicles Nerve 1 Nerve 2
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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 Acetylcholine is natural messenger for both receptor types Activates cholinergic receptors at nerve synapses and on skeletal muscle Activates cholinergic receptors on smooth muscle and cardiac muscle Nicotine L-(+)-Muscarine
Slide 19-

Peripheral nervous system CNS (Somatic) CNS (Autonomic) Sympathetic Parasympathetic NA Ach (N) Synapse Ach (N) Ach (N) Ach (N) Ach (M) Adrenal medulla Adrenaline Skeletal Muscle SOMATIC Synapse AUTONOMIC Smooth Muscle Cardiac Muscle
Slide 20-

Cell membrane Five glycoprotein subunits traversing cell membrane Receptor Binding site Messenger Control of Cationic Ion Channel: 4.1 Nicotinic receptor Cell membrane Induced fit ‘Gating’ (ion channel opens)
Slide 21-

The binding sites a a g d b Two ligand binding sites mainly on a-subunits Ion channel 2xa, b, g, d subunits Binding sites 4.1 Nicotinic receptor Cell membrane a a d b g
Slide 22-

Activation of a signal protein Receptor binds messenger leading to an induced fit Opens a binding site for a signal protein (G-protein) closed messenger induced fit open 4.2 Muscarinic receptor - G Protein coupled receptor G-protein bound G-protein split
Slide 23-

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 (closed) active site (open) Enzyme Enzyme Intracellular reaction 4.2 Muscarinic receptor - G Protein coupled receptor subunit
Slide 24-

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
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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
Slide 26-

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
Slide 27-

Acetoxy Ethylene bridge 4 o Nitrogen Acetoxy Ethylene bridge Nitrogen 6. SAR for acetlcholine Quaternary nitrogen is essential Bad for activity
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Distance from quaternary nitrogen to ester is important Ethylene bridge must be retained 6. SAR for acetylcholine Bad for activity Acetoxy Ethylene bridge 4 o Nitrogen Acetoxy Ethylene bridge Nitrogen
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Ester is important 6. SAR for acetylcholine Bad for activity Acetoxy Ethylene bridge 4 o Nitrogen Acetoxy Ethylene bridge Nitrogen
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Minimum of two methyl groups on quaternary nitrogen 6. SAR for acetylcholine Bad for activity Active Acetoxy Ethylene bridge 4 o Nitrogen Acetoxy Ethylene bridge 4 o Nitrogen
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Methyl group of acetoxy group cannot be extended 6. SAR for acetylcholine Bad for activity Acetoxy Ethylene bridge 4 o Nitrogen Acetoxy Ethylene bridge Nitrogen
Slide 32-

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 6. SAR for acetylcholine Acetoxy Ethylene bridge 4 o Nitrogen
Slide 33-

Trp-307 Asp311 Trp-613 Trp-616 Asn-617 7. Binding site (muscarinic) hydrophobic pocket hydrophobic pocket hydrophobic pockets
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Trp-307 Asp311 Trp-613 Trp-616 Asn-617 7. Binding site (muscarinic) H-bonds Ionic bond vdw vdw vdw
Slide 35-

Possible induced dipole dipole interaction between quaternary nitrogen and hydrophobic aromatic rings in binding site N+ induces dipole in aromatic rings 7. Binding site (muscarinic) d - d - d + d +
Slide 36-

Several freely rotatable single bonds Large number of possible conformations Active conformation does not necessarily equal the most stable conformation 8. Active conformation of acetylcholine
Slide 37-

Rigid Analogues of acetylcholine Rotatable bonds ‘locked’ within ring Restricts number of possible conformations Defines separation of ester and N 8. Active conformation of acetylcholine Muscarinic receptor Nicotinic receptor
Slide 38-

Neighbouring group participation Increases electrophilicity of carbonyl group Increases sensitivity to nucleophiles 9. Instability of acetylcholine
Slide 39-

10. Design of cholinergic agonists Requirements Correct size Correct pharmacophore - ester and quaternary nitrogen Increased stability to acid and esterases Increased selectivity
Slide 40-

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 10. Design of cholinergic agonists
Slide 41-

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 asymmetric centre hinders binding to esterases and provides a shield to nucleophilic attack
Slide 42-

10. Design of cholinergic agonists Use of electronic factors Replace ester with urethane Stabilises the carbonyl group =
Slide 43-

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 Carbachol
Slide 44-

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 Bethanechol
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10. Design of cholinergic agonists Nicotinic selective agonist
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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
Slide 47-

Peripheral nervous system CNS (Somatic) CNS (Autonomic) Sympathetic Parasympathetic NA Ach (N) Synapse Ach (N) Ach (N) Ach (N) Ach (M) Adrenal medulla Adrenaline Skeletal Muscle SOMATIC Synapse AUTONOMIC Smooth Muscle Cardiac Muscle