Transcript Acetylcholine & Alzheimer`s Disease

Alzheimer’s Disease &
Acetylcholine
Presentation by: Huy Nguyen
Chemistry 12B
Instructor: Dr. Adamczeski
Fall-2006
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Out line
• What is Acetylcholine?
• Synthesis of Acetylcholine
• How does Acetylcholine work in nervous
system
• Acetylcholine receptors
• Degradation of Acetylcholine
• Alzheimer’s disease
• Drug development
• Reference
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What is Acetylcholine?
• The first known neurotransmitter, discovered
in 1920’s.
• It is the neurotransmitter at nerve-muscle
connections and at nervous system synapses.
• An organic compound:
CH3CO2CH2CH2N+(CH3)3
http://www.cas.org/motw/acetylcholinepub.gif
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Synthesis of Acetylcholine (Ach)
• Acetylcholine is a simple molecule synthesized from
choline and acetyl-CoA through the action of choline
acetyltransferase in cholinergic neurons.
Acetyl-CoA
Choline
http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm
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How does Ach work in nervous
system?
• Action potential reaches the terminal button of
a presynaptic neuron.
• Ca2+, stimulates the exocytosis of vesicles
containing Ach, which is released into the
synaptic cleft.
• Ach reaches the other neuron membrane, then
binds to the Ach receptors and activates them
to open ion channels to create new action
potential.
•http://en.wikipedia.org/wiki/intergal-membrane-protine
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http://en.wikipedia.org/wiki/intergal-membrane-protine
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Acetylcholine receptors
• Nicotinic receptors:
– S – Nicotine: C10H14N2
http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm
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Acetylcholine receptors
• Muscarinic receptors
– Muscarine: C9H20ON +
http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm
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Degradation of Acetylcholine
The destruction of Acetylcholine by Acetylcholinesterase and the Reuptake of Choline
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http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html
Ach
O
N
O
H3C
CH3
O
CH3
CH3
N
O
H3C
CH3
H-O-SER-ACHE
CH3
CH3
H-O-SER-ACHE
(Achase)
CH3
OH
H3C
O
H3C
OH
H-O-SER-ACHE
(Achase)
H3C
O
O
SER-ACHE
H O
N
Choline
CH3
CH3
H3C
CH3
H
O
O-SER-ACHE
CH3
CH3
O-SER-ACHE
CH3
O
N
O
N
CH3
CH3
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Alzheimer’s Disease
•
The cause of Alzheimer's Disease is not fully understood. It is believed there may be
genetic (hereditary) factors involved, with a breakdown of proteins resulting in the
formation of protein deposits (senile plaques) within the brain.
•
Acetylcholine is required for the normal functioning of the brain cells and, as levels of
the chemical decrease, plaques form creating bundles of fibers (neurofibrillary
tangles).
•
Alzheimer’s disease is characterized by amyloid plaques (clumps of fibers) and tangles
of fibers in brain.
•
Alzheimer’s disease may disrupt normal thinking and memory by blocking the
massages transferred through neurons by neurotransmitters.
•
A disorder that primarily affects the elderly and is associated with memory loss.
•
Only Ach and the enzyme Choline acetyltransferase were found to be reduced in the
patients with Alzheimer’s disease.
http://health.yahoo.com – Yahoo! Health Encyclopedia: Alzheimer’s disease Overview
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Drug development
• Focus on the
development of
centrally active
muscarinic receptor
agonists for the
treatment of the
Alzheimer’s disease.
http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm
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Drug development
• Acetylcholinesterase is a tetrameric protein
which catalyzes the hydrolysis of Ach.
• The more easier way to approach the treatment
of Alzheimer’s disease is to inhibit the activity
of the Acetylcholinesterase in the brain.
• The general concept to inhibit
Acetylcholinesterase is to protect its active –
OH group by more active carbonyl
compounds.
http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm
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Acetylcholinesterase Inhibitors
• Inhibitor blocking
hydrolysis.
• Inhibitors that acylate
the serine-OH group,
forming a carbamyl
ester
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Acetylcholinesterase Inhibitors
• Donepezil is a good
inhibitor and good CNS
penetration.
• Rivastigmine has been
approved for use in
Europe
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References
•
•
•
•
•
•
http://www.cas.org/motw/acetylcholinepub.gif
http://web6.duc.auburn.edu/
http://en.wikipedia.org/wiki/intergal-membrane-protine
http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html
http://www.chemistry.org/
http://www.neurosci.pharm.utoledo.edu/MBC3320/muscarinic.htm
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