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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. Disease : Alzheimer’s Disease & Stats. Alzheimer’s is a form of dementia 2012 Statistics

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acetylcholinesterase inhibitors in the treatment of alzheimer s and dementia

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

disease alzheimer s disease stats
Disease: Alzheimer’s Disease & Stats

Alzheimer’s 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 Alzheimer’s sufferers are women
  • 6th 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)

disease some alzheimer s etiologies and possible t herapeutic pathways
Disease: Some Alzheimer’s Etiologies and Possible Therapeutic pathways

Degradation of Acetylcholine

disease drugs history of az drugs for different pathways
Disease/Drugs: History of AZ Drugs for Different Pathways
  • Acetylcholinesterase inhibitors
    • 1993: Tacrine approved for mild to moderate Alzheimer’s symptoms
    • 1996: Donepezil approved for mild to severe Alzheimer’s symptoms
    • 2000: Rivastigmine approved for mild to moderate Alzheimer’s symptoms
    • 2001: Galantamineapproved for mild to moderate Alzheimer’s symptoms
  • Namenda (NMDA receptor antagonist)
    • 2003: Namenda approved for moderate to severe Alzheimer’s symptoms
    • 2010: Namenda XR approved for moderate to severe Alzheimer’s symptoms
target 1 ache mechanism of action
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
target acetylcholinesterase
Target: Acetylcholinesterase
  • 2 general classes of molecular forms
    • Simple homomericoligomers 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
target acetylcholinesterase1
Target: Acetylcholinesterase
  • Acetylcholinesterase rapidly hydrolyzes Ach
    • Terminates transmission at cholinergic synapses
  • Alzheimer’s may involve depletion of Ach
    • Inhibition of acetylcholinesterase could help symptoms
  • Active Site
    • Esteraticsubsite: catalytic machinery
    • Anionic subsite: binds quaternary group of Ach
    • Peripheral anionic subsite: 14Å from anionic subsite
      • Enhanced potency if drug can span both active sites
target acetylcholinesterase site
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
drug molecules
Drug Molecules




  • Tacrine has no chiral centers
  • Galantamine has three chiral centers and the (S,R,S) conformer is the naturally occurring form
  • Donepezil’s two stereoisomers show activity but its R-enantiomer has more activity
drug tacrine
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
drug groups donepezil
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 π–π 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
drug groups galantamine
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 inhibitor’s 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
drugs side effects
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
drug drug interactions
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
future treatments
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 Alzheimer’s
    • NSAIDs have had variable effects
  • 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 Alzheimer’s and does not address the underlying pathophysiology of the disease state
  • New treatments will likely target other factors involved in Alzheimer’s – drugs targeting amyloid-beta plaques and tau proteins are currently being developed
  • Combination therapies

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A. Koster, Hemmung der cholinesterasen in verscheidenenorganendurcheserin, galanthamine und tacrin; conzentrations-wirkungsbeziehungen, bedeuting fir die therapeutischanwendung. Dissertation 1994; MedezinsicheFakultat der Humboldt Univzu Berlin.

Abagyan, R.,Physical Pharmacology. (accessed March 5, 2013).

"Alzheimer's Disease Treatments." Alzheimer's Disease Treatments. BrightFocus Foundation, 4 Oct. 2012. Web. 07 Mar. 2013.

"Alzheimer's Treatments: What's on the Horizon?" Mayo Clinic. Mayo Foundation for Medical Education and Research, 06 Mar. 2013. Web. 07 Mar. 2013.

"Drug Bank: Donepezil." DrugBank. GenomeQuest, 8 Feb. 2013. Web. 7 Mar. 2013.

"Drug Bank: Galantamine." DrugBank. GenomeQuest, 8 Feb. 2013. Web. 7 Mar. 2013.

"Drug Bank: Tacrine." DrugBank. GenomeQuest, 8 Feb. 2013. Web. 7 Mar. 2013.

Greenblatt, H., et al. "Structure of AcetylcholinesteraseComplexed with (-)-galanthamine at 2.3 A Resolution." Federation of European Biochemical Societies 463 (1999): 321-26. FEBS Letters, 8 Nov. 1999. Web. 7 Mar. 2013.

Harel, M., et al. "Quaternary Ligand Binding to Aromatic Residues in the Active-site Gorge of Acetylcholinesterase." ProcNatlAcadSci U S A 90.19 (1993): 9031-035. PubMed. Web. 7 Mar. 2013.

Kryger, G., et al. "Structure of AcetylcholinesteraseComplexed with E2020 (Aricept®): Implications for the Design of New Anti-Alzheimer Drugs." Structure 7.3 (1999): 297-307. Elsevier Science Ltd., 1 Mar. 1999. Web. 7 Mar. 2013.

Maccioni, R., Perry, G., Current Hypotheses and Research Milestones in Alzheimer's Disease. New York: Springer, 2009. Print.

Massouli, J Molecular forms and anchoring of acetylcholinesterase. In, Cholinesterases and Cholinesterase Inhibitors. (Giacobini E, ed) Martin Dunitz, London, 2000 pp. 81-103

Sussman, J.. et al. "Atomic Structure of Acetylcholinesterase from Torpedo Californica: A Prototypic Acetylcholine-Binding Protein." Science 253 (1991): 253-61. 21 Dec. 2006. Web. 7 Mar. 2013.