Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s and Dementia Pharmaceutical...
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Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s and Dementia Pharmaceutical Chemistry II – SSPPS 222 Based on Presentation from : Victor Ramos, Lisa Ferris, and Sarah Brown
Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s and Dementia Pharmaceutical Chemistry II – SSPPS 222 Based on Presentation from : Victor
Acetylcholinesterase Inhibitors in the Treatment of Alzheimers
and Dementia Pharmaceutical Chemistry II SSPPS 222 Based on
Presentation from : Victor Ramos, Lisa Ferris, and Sarah Brown
Slide 2
Disease: Alzheimers Disease & Stats Alzheimers is a form of
dementia 2012 Statistics 5.4 million citizens (5.2 million 65 and
older) One in eight older Americans By 2025, 6.7 million (30%
increase) 2/3 of Alzheimers sufferers are women 6 th leading cause
of death in the United States Payments for care are estimated to
exceed $200 billion 80% of care is delivered by family (valued at
over $210 billion)
http://www.alz.org/downloads/facts_figures_2012.pdf
Slide 3
Disease: Some Alzheimers Etiologies and Possible Therapeutic
pathways NameEtiology Choliner gic Alzheimers is characterized by
an acetylcholine deficiency due to atrophy and degeneration of
cholinergic neurons AmyloidBeta-amyloid peptides, partial
aggregates and plaques (or a close relative of A) build up in the
brain and change synapses, disrupting communication TauTau protein
is hyperphosphorylated, and this initiates a cascade in which
neurofibrillary tangles destroy the transport system inside neurons
Degradation of Acetylcholine
Slide 4
Disease/Drugs: History of AZ Drugs for Different Pathways
Acetylcholinesterase inhibitors 1993: Tacrine approved for mild to
moderate Alzheimers symptoms 1996: Donepezil approved for mild to
severe Alzheimers symptoms 2000: Rivastigmine approved for mild to
moderate Alzheimers symptoms 2001: Galantamine approved for mild to
moderate Alzheimers symptoms Namenda (NMDA receptor antagonist)
2003: Namenda approved for moderate to severe Alzheimers symptoms
2010: Namenda XR approved for moderate to severe Alzheimers
symptoms
Slide 5
Target 1: AChE: Mechanism of Action Acetylcholinesterase breaks
down Ach into choline and an acetate through hydrolysis
Acetylcholinesterase inhibitors block this reaction in several
regions of the brain There is a significant correlation between
acetylcholinesterase inhibition and observed cognitive
improvement
Slide 6
Target: Acetylcholinesterase 2 general classes of molecular
forms Simple homomeric oligomers of catalytic subunits Founds as
soluble species in cell Exported Heteromeric associations of
catalytic subunits with structural subunits Found in neuronal
synapses Tetramer of catalytic subunits disulfide linked to a 20kDa
lipid-linked subunit Outer surface of cell membrane
Slide 7
Target: Acetylcholinesterase Acetylcholinesterase rapidly
hydrolyzes Ach Terminates transmission at cholinergic synapses
Alzheimers may involve depletion of Ach Inhibition of
acetylcholinesterase could help symptoms Active Site Esteratic
subsite: catalytic machinery Anionic subsite: binds quaternary
group of Ach Peripheral anionic subsite: 14 from anionic subsite
Enhanced potency if drug can span both active sites
Slide 8
Target: Acetylcholinesterase Site Contains catalytic triad
Located at bottom of aromatic gorge Deep, narrow cavity 40% lined
by rings of 14 aromatic amino acids Primary site of interaction
between quaternary group of Ach and acetylcholinesterase is
aromatic ring of Trp-84 Trp-84 and Phe-330 part of anionic subsite
Trp-275 part of peripheral anionic subsite
Slide 9
Drugs AZ-AChE: Chemical Properties Brand
NameCognexAriceptRazadyne Generic NameTacrineDonepezilGalantamine
Molecular Structure Salt Ionization/Delivery Kd3.5 nM12 nM200 nM
Reversible or Covalent?/timing Drug TargetAcetylcholinesterase,
Butyrylcholinesterase AcetylcholinesteraseAcetylcholinesterase,
Butyrylcholinesterase
Slide 10
Drug Molecules Donepezil Tacrine Galantamine Tacrine has no
chiral centers Galantamine has three chiral centers and the (S,R,S)
conformer is the naturally occurring form Donepezils two
stereoisomers show activity but its R- enantiomer has more
activity
Slide 11
Drug: Tacrine Normally, phenyl ring of Phe-330 lies parallel to
surface of gorge When tacrine binds, it makes contact with the
bound ligand Ring of Phe-330 is rotated about both X1 and X2
Tacrine is thus sandwiched between between the rings of Phe-330 and
Trp-84 Recall Trp-84 is primary site of interaction between Ach and
acetylcholinesterase
Slide 12
Drug Groups: Donepezil Three segments of Donepezil, all
interact with Acetylcholinesterase gorge Dimethoxyindanone Inandone
ring has pi-pi interactions with indole ring of Trp279 Piperidine
Cation-pi interaction with Phe330 Ring N makes H bonds with water
which makes H bonds with Tyr121 Benzyl Parallel stacking with the
Trp84 indole, Makes an aromatic H-bonds with water molecules that
H-bond to the residues of the oxyanion hole, namely with Gly118 N,
Gly119, Gly201 N, and Ser200 Occupies the binding site for
quaternary ligands such a ACh
Slide 13
Drug Groups: Galantamine The inhibitor spans the active site
gorge, including the acyl binding site Hydrogen bonding Two H-bonds
form between the hydroxyl of the inhibitor and Glu-199 and Ser-200
and the inhibitors oxygen molecule Water molecules Rest of
interactions are Non-Polar Notable that galantamine lacks the
characteristic cation-pi interaction with Phe-330 Pi-stacking
occurs between the double bonds in the cyclohexene ring of GAL and
the indole ring of Trp-84 No charge-charge interactions
Slide 14
Polar and Non-Polar Characteristics TacrineGalantamineDonepezil
H-bond donors210 H-bond acceptors 244 Polar Atoms244 Non-Polar
Atoms131724 Polar Surface Area 38.91 241.93 238.77 2 Physiological
Charge +1 Water Solubility0.136 g/l1.70 g/l0.00291 g/L
logP3.131.84.14
Drugs: Side Effects Tacrine Causes elevated hepatic enzymes
(CYP1A2) and is hepatotoxic Tacrine metabolite is cytotoxic Off
market Galantamine Abdominal pain, diarrhea, nausea related to
cholinergic effects Resolve with continued treatment Donepezil Well
tolerated at 5 mg/day 13% discontinuation rate at 10 mg/day.
Gastrointestinal side effects are most common, related to
cholinergic effects All acetylcholinesterase inhibitors act through
similar mechanisms, so GI side effects are similar, with severity
depending on the dose administered Increased acetylcholine
over-stimulates cholinergic receptors in the GI tract to cause
secretory and motor activity
Slide 17
Drug-Drug Interactions CYP34A inhibitors like erythromycin,
cimetidine, and saquinavir increase bioavailability of the drugs
and lead to increased adverse effects The same is true for CYP2D6
and CYP1A2 inhibitors In contrast, inducers of these metabolic
enzymes like phenytoin and rifampicin will decrease bioavailability
and lead to limited efficacy of the drugs
Slide 18
Future Treatments Immunizations that utilize the immune system
to attack beta-amyloid plaques This went to clinical trials but was
stopped when some participants developed acute brain inflammation
Anti-amyloid antibodies derived from other sources infused into the
blood via IV Preventing neurofibrillary tangles Reducing chronic
neuron inflammation associated with Alzheimers NSAIDs have had
variable effects
Slide 19
Conclusion These drugs effectively inhibit acetylcholinesterase
from hydrolyzing acetylcholine into choline and an acetyl group
However, this may or may not be effective in prolonging onset or
reducing symptom severity in Alzheimers and does not address the
underlying pathophysiology of the disease state New treatments will
likely target other factors involved in Alzheimers drugs targeting
amyloid-beta plaques and tau proteins are currently being developed
Combination therapies
Slide 20
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