1. CHEM E-120 Harvard University Extension School
Neurodegenerative Disorders
Alzheimer’s Disease
April 6, 2011
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CHEM E-120

2. Alzheimer’s Disease Most prevalent of the neurodegenerative diseases
Affects ~ million individuals worldwide
Age onset ~ 60 – 65 years, risk of developing Alzheimer’s doubles every 5 years after age 65 with a 50% chance after age 85.
8th leading cause of death
Main clinical symptom is dementia
early memory impairment
episodic memory
progressive decline in executive function – reasoning, etc
drastic alterations in personality – aggressive behavior
DSM-IV classifies several forms of dementia
No diagnostic tool premortem except clinical dementia rating (CDR)
Postmortem analysis is characterized by the identification of neurofibrillary tangles (NFT) and amyloid plaques.
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3. Cholinergic Hypothesis - AD
Based on finding reduced activity of choline acetyltransferase activity and loss of cholinergic neurons in the forebrain. Reduction in amount of acetylcholine.
Cholinergic system appears important in
cognitive function: attention, memory
noncognitive function: depression, psychosis, aggression, sleep
Acetylcholine (ACh) binds to muscarinic receptors and nicotinic (nAChR) Na+ channels.
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4. Neurotransmitters - Acetylcholine
mnemonic function
neurofibrally tangles
appear here first
in early satge AD
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5. 2. M1 agonist (stimulates cognitive function) 3. NAChR agonists
Loss of ACh
How to increase it?
1. Inhibition of ACHE
2. M1 agonist (stimulates cognitive function)
3. NAChR agonists
α4β2 agonist
predominate NACh subunit in brain
partial agonist Varenicline
(7)5 agonist inc Ca2+ permeability
agonist increase cognition
4. 5-HT1A antagonist increase ACh and glutamate
Comprehensive Medicinal Chemistry II
Chapter 6.08
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6. Mediciation Development Alzheimer’s Disease
1. Acetylcholineesterase inhibitors (4 approved for use)
Tacrine (Cognex)
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne, Reminyl)
2. NMDA noncompetitive antagonist (Approved)
Memantine (Namenda)
reduces Ca2+ influx into neurons, excess Ca2+ is cytotoxic
3. β-Secretase inhibitors
4. GSK-3 inhibitors (Annual Reports in Med. Chem. 2010, 44, 3
5. 5HT1A antagonists
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7. Acetylcholinesterase
Acetylcholinesterase (ACHE) is a serine esterase enzyme
ACHE has an anionic binding site which attracts the positively charged quaternary ammonium group of ACH. A serine then attacks and cleaves the ester. This is an example of general base catalysis.
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8. Phe297 Phe295 vs aliphatic in BChE catalytic triad Glu202 quat site
van der Waals surface map of acetylcholine in active site of AChE
inhibitor binding site
Phe297
Phe295
vs aliphatic
in BChE
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catalytic triad
CHEM E-120
Basic Neurochemistry p. 195
Glu202 quat site

9. Acta Biologica Hungarica 54 (2), pp. 183–189 (2003)
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10. Donepezil - Aricept Approved in 1997
Annual Reports in Medicinal Chemistry 1998, 33, 332
Jpn. J. Pharmacol. 89, 7 – 20 (2002)
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11. Discovery of Donepezil
1 found through random screening
prepared about 700 analogs
benzylpiperizine to benzylpiperidine
replacement of ether
4 poor bioavailability and short duration
of action
Jpn. J. Pharmacol. 89, 7 – 20 (2002)
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12. Discovery of Donepezil
7 replace amide by ketone
6 cyclic amide better inhibition
than 5
leads to 8
IC50 less than 4 but longer duration of action
SAR
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13. Discovery of Donepezil
ring size
carbonyl
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14. Discovery of Donepezil
p-methoxy
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15. Discovery of Donepezil
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16. Discovery of Donepezil
location and number of N’s
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17. Discovery of Donepezil
pKa!
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18. Discovery of Donepezil
Tacrine oral ID50 = 9.5 mg/kg
oral ID50 = 2.6 mg/kg
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19. Discovery of Donepezil
move from light to dark chamber (foot shock)
learn: avoid dark chamber
no learning
MS cholinergic projections to hippocampus
equivalent to Meynert nucleus in humans
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20. Discovery of Donepezil
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21. Discovery of Donepezil
Result of J-CGIC
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22. Structure March 1999, 7:297–307
π-π stacking
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23. Structure March 1999, 7:297–307
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24. Amyloid Plaque Formation
Insoluble, neurotoxic, protein clusters formed from Amyloid Precursor Protein (APP)
770 AA
AA669 Asp
C terminus
intracellular
N terminus
extracellular
BACE β-secretase
Β-CFT
AA669
AA770
γ-secretase
AChE
Aβ – β-amyloid1-40(42)
fibril
peripheral site
of AChE
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25. BACE Inhibitors 2-Amino-3,4-dihydroquinazolines
High-throughput hit from a screen
of their corporate compound
collection
J. Med. Chem. 2007, 50, Johnson & Johnson
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26. BACE - 2-Amino-3,4-dihydroquinazolines
First obtained a X-ray crystal of 1 bound to BACE-1
1 forms a U shaped conformation in active site
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27. BACE - 2-Amino-3,4-dihydroquinazolines
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28. 5-HT1A Antagonists Lecozatan – Selective 5-HT1A Antagonist
It has been suggested that the serotonergic system may be hyperactive in AD as a result of enhanced turnover of serotonin. This will ultimately result in the reduction of activity of cortical pathways by the binding of serotonin to autoreceptors on presynaptic neurons.
It has been found that 5-HT1A antagonists can facilitate glutamatergic activity and cholinergic activity which leads to a reduction in cognitive deficits.
The Potential Utility of 5-HT1A Receptor Antagonists in the Treatment of Cognitive Dysfunction Associated with Alzheimer’s Disease Current Pharmaceutical Design, 2002, 8,
Lecozatan – Selective 5-HT1A Antagonist
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29. WAY100135 – Selective 5-HT1A Antagonist
Arylpiperazines reported to be high-affinity 5-HT1A ligands (JMC 1988, 31, 1968)
Eur. J. Pharmacol. 1988, 154, 339
In 1993 WAY was reported as the
first true selective antagonist of 5-HT1A
Eur. J. Pharmacol. 1993, 237, 283
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30. WAY100135 – Selective 5-HT1A Antagonist Evidence for presynaptic antagonist activity (autoreceptor)
serotonin at 5-HT1A presynaptic inhibits firing
Drug ID50 (μg/kg i.v.)
8-OH-DPAT (agonist)
BMY7378 (partial agonist) 12
NAN-190 (partial agonist)
MDL73005EF (“)
(±)WAY >2500
(+)WAY >600
(-)WAY >1000
inhibitory effect
serotonin is blocked
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31. WAY100135 – Selective 5-HT1A Antagonist Evidence for presynaptic antagonist activity
The 5-HT1A agonist 8-OH-DPAT induces hypothermia in mice.
An antagonist should prevent this in a dose-dependent manner
(±)WAY ED50 = 2.0 mg/kg s.c.
(+)WAY ED50 = 1.5 mg/kg s.c.
(-)WAY ineffective up to 30 mg/kg
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32. WAY100135 – Selective 5-HT1A Antagonist Evidence for postsynaptic antagonist activity
5-CT is a 5-HT1A
agonist that:
Inhibits the electrically
stimulated contraction
of muscle
rightward shift that is
indicative of antagonism
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33. WAY100135 – Selective 5-HT1A Antagonist Evidence for postsynaptic antagonist activity
(+)
The 8-OH-DPAT syndrome
Due to 5-HT activation
Extended flat body posture
Forepaw treading
Hyperlocomotion
(±)
(-)
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34. WAY100635 Drug IC50 (nM) pA2 (5-CT) ED50 (antag. Induced hypothermia)
(±)WAY mg/kg
(+)WAY
(-)WAY
WAY mg/kg
>100 fold selective vs other 5-HT receptors and 35 other receptors/transporters
Eur. J. Pharmacol. 1995, 281, 81-88
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35. Lecozatan – Selective 5-HT1A Antagonist
WAY lacked
bioavailability.
Modification of the amide
portion and N-phenyl
portion.
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36. Lecozatan – Selective 5-HT1A Antagonist
Though not the most potent
in vitro antagonist, 11c showed
most potency in vivo
Rats trained to respond to
fixed ratio-30 schedule of
food presentation to receive a
food pellet.
Agonist 8-OH-DPAT reduces
response rate.
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37. Lecozatan – Selective 5-HT1A Antagonist
J. Pharmacology and Experimental Therapeutics 2005, 314, 1274
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38. Lecozatan – Selective 5-HT1A Antagonist
In vivo microdialysis
in conscious rats
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39. Lecozatan – Selective 5-HT1A Antagonist
Time dependent increase in glutamate levels in dentate gyrus by in vivo microdialysis
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40. Lecozatan – Selective 5-HT1A Antagonist
Time dependent increase in acetylcholine levels in hippocampus by in vivo microdialysis
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41. Lecozatan – Selective 5-HT1A Antagonist
1.0 mg/kg
Lecozotan enhances cognitive function in the aged rhesus monkey as assessed by DMTS
(delayed matching-to-sample) performance efficiency.
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42. Lecozatan – Selective 5-HT1A Antagonist
binding of
11C-WAY
Nature Clinical Pharmacology and Therapeutics 2008, 83, 86
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43. Lecozatan – Selective 5-HT1A Antagonist
Study shows Lecozotan is readily absorbed into the brain and binds to
5-HT1A receptors regardless of age and is not affected by AD being present
Nature Clinical pharmacology and Therapeutics 2008, 83, 86
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