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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

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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

    Drugs az ache chemical properties

    Drugs AZ-AChE: Chemical Properties

    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

    Polar and non polar characteristics

    Polar and Non-Polar Characteristics

    Pharmacokinetic properties

    Pharmacokinetic Properties

    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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    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.

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