Acetylcholinesterase Inhibitors in the Treatment of Alzheimers and Dementia

Acetylcholinesterase Inhibitors in the Treatment of Alzheimers and DementiaPharmaceutical Chemistry II SSPPS 222Based on Presentation from : Victor Ramos, Lisa Ferris, and Sarah BrownDisease: Alzheimers Disease & StatsAlzheimers is a form of dementia 2012 Statistics5.4 million citizens (5.2 million 65 and older)One in eight older AmericansBy 2025, 6.7 million (30% increase)2/3 of Alzheimers sufferers are women6th leading cause of death in the United StatesPayments for care are estimated to exceed $200 billion80% of care is delivered by family (valued at over $210 billion)http://www.alz.org/downloads/facts_figures_2012.pdf

Longer life expectancies, more people who are old (baby boomers)2Disease: Some Alzheimers Etiologies and Possible Therapeutic pathwaysNameEtiologyCholinergicAlzheimers is characterized by an acetylcholine deficiency due to atrophy and degeneration of cholinergic neuronsAmyloidBeta-amyloid peptides, partial aggregates and plaques (or a close relative of A) build up in the brain and change synapses, disrupting communicationTauTau protein is hyperphosphorylated, and this initiates a cascade in which neurofibrillary tangles destroy the transport system inside neurons

Degradation of Acetylcholine**there are others, these are the main ones!Most drug therapies (including ours) is based on cholinergic hypothesisAmyloid: 19913Disease/Drugs: History of AZ Drugs for Different PathwaysAcetylcholinesterase inhibitors1993: Tacrine approved for mild to moderate Alzheimers symptoms1996: Donepezil approved for mild to severe Alzheimers symptoms2000: Rivastigmine approved for mild to moderate Alzheimers symptoms2001: Galantamine approved for mild to moderate Alzheimers symptoms

Namenda (NMDA receptor antagonist)2003: Namenda approved for moderate to severe Alzheimers symptoms2010: Namenda XR approved for moderate to severe Alzheimers symptoms

Nmda receptor antagonists reduce activity of glutamate in the brain4Target 1: AChE: Mechanism of ActionAcetylcholinesterase breaks down Ach into choline and an acetate through hydrolysisAcetylcholinesterase inhibitors block this reaction in several regions of the brainThere is a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement

http://www.ncbi.nlm.nih.gov/pubmed/151327135Target: Acetylcholinesterase2 general classes of molecular formsSimple homomeric oligomers of catalytic subunitsFounds as soluble species in cellExportedHeteromeric associations of catalytic subunits with structural subunitsFound in neuronal synapsesTetramer of catalytic subunits disulfide linked to a 20kDa lipid-linked subunitOuter surface of cell membrane

Massoulie, 2000; Taylor et al., 20006Target: AcetylcholinesteraseAcetylcholinesterase rapidly hydrolyzes AchTerminates transmission at cholinergic synapsesAlzheimers may involve depletion of AchInhibition of acetylcholinesterase could help symptomsActive SiteEsteratic subsite: catalytic machineryAnionic subsite: binds quaternary group of AchPeripheral anionic subsite: 14 from anionic subsiteEnhanced potency if drug can span both active sites

http://www.nature.com/nrn/journal/v2/n4/images/nrn0401_294a_f1.gif

Harel M, Schalk I, blah blah7Target: Acetylcholinesterase Site

Contains catalytic triadLocated at bottom of aromatic gorgeDeep, narrow cavity40% lined by rings of 14 aromatic amino acidsPrimary site of interaction between quaternary group of Ach and acetylcholinesterase is aromatic ring of Trp-84Trp-84 and Phe-330 part of anionic subsiteTrp-275 part of peripheral anionic subsite

http://www.ncbr.muni.cz/pict/research/acetylcholinesterase_02.png

Harel M, Schalk I, blah blah

8Drugs AZ-AChE: Chemical PropertiesBrand NameCognexAriceptRazadyneGeneric NameTacrineDonepezilGalantamineMolecular StructureSaltIonization/DeliveryKd3.5 nM12 nM200 nMReversible or Covalent?/timingDrug TargetAcetylcholinesterase, ButyrylcholinesteraseAcetylcholinesteraseAcetylcholinesterase, Butyrylcholinesterase

Drug Molecules

DonepezilTacrineGalantamineTacrine has no chiral centersGalantamine has three chiral centers and the (S,R,S) conformer is the naturally occurring formDonepezils two stereoisomers show activity but its R-enantiomer has more activityDrug: Tacrine

Normally, phenyl ring of Phe-330 lies parallel to surface of gorgeWhen tacrine binds, it makes contact with the bound ligandRing of Phe-330 is rotated about both X1 and X2Tacrine 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

Harel M, Schalk I, blah blah

11Drug Groups: DonepezilThree segments of Donepezil, all interact with Acetylcholinesterase gorgeDimethoxyindanone Inandone ring has pi-pi interactions with indole ring of Trp279PiperidineCation-pi interaction with Phe330Ring N makes H bonds with water which makes H bonds with Tyr121BenzylParallel 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

The inhibitor spans the active site gorge, including the acyl binding site Hydrogen bondingTwo H-bonds form between the hydroxyl of the inhibitor and Glu-199 and Ser-200 and the inhibitors oxygen moleculeWater molecules Rest of interactions are Non-PolarNotable that galantamine lacks the characteristic cation-pi interaction with Phe-330Pi-stacking occurs between the double bonds in the cyclohexene ring of GAL and the indole ring of Trp-84No charge-charge interactions

Polar and Non-Polar CharacteristicsTacrineGalantamineDonepezil H-bond donors210H-bond acceptors244Polar Atoms244Non-Polar Atoms131724Polar Surface Area38.91 2

41.93 2

38.77 2

Physiological Charge+1+1+1Water Solubility0.136 g/l 1.70 g/l0.00291 g/LlogP3.131.84.14DrugBank tacrine, galantamine, donepezil14Pharmacokinetic PropertiesTacrine GalantamineDonepezilAdministration20 mg, 4x daily8-12 mg, 2x daily10 mg, 1x dailyTmax0.5 - 2 hours0.5 1.5 hours3 5 hoursAUC83.2 +/- 26.7 g h/LN/R357.7 +/- 64.0 g h/L

Bioavailability17-24%85-100%100%Volume of Distribution3.7 5.0 L/kg0.83 2.75 L/kg12 L/kgHalf-life2-4 hours7 hours70 hoursProtein binding75%18%96%Metabolic EliminationCYP2D6, CYP1A2CYP2D6, CYP3A4

CYP2D6, CYP3A4

http://www.nature.com/clpt/journal/v46/n6/pdf/clpt1989199a.pdf tacrine15Drugs: Side EffectsTacrineCauses elevated hepatic enzymes (CYP1A2) and is hepatotoxicTacrine metabolite is cytotoxicOff marketGalantamineAbdominal pain, diarrhea, nausea related to cholinergic effectsResolve with continued treatmentDonepezilWell 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 administeredIncreased acetylcholine over-stimulates cholinergic receptors in the GI tract to cause secretory and motor activityDrug-Drug InteractionsCYP34A inhibitors like erythromycin, cimetidine, and saquinavir increase bioavailability of the drugs and lead to increased adverse effectsThe same is true for CYP2D6 and CYP1A2 inhibitorsIn contrast, inducers of these metabolic enzymes like phenytoin and rifampicin will decrease bioavailability and lead to limited efficacy of the drugsFuture TreatmentsImmunizations that utilize the immune system to attack beta-amyloid plaquesThis went to clinical trials but was stopped when some participants developed acute brain inflammationAnti-amyloid antibodies derived from other sources infused into the blood via IVPreventing neurofibrillary tanglesReducing chronic neuron inflammation associated with AlzheimersNSAIDs have had variable effectsConclusionThese drugs effectively inhibit acetylcholinesterase from hydrolyzing acetylcholine into choline and an acetyl groupHowever, 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 stateNew treatments will likely target other factors involved in Alzheimers drugs targeting amyloid-beta plaques and tau proteins are currently being developedCombination therapies References"2012 Alzheimer's Disease Facts and Figures." Alzheimer's and Dementia 8.2 (2012): 1-67. 2012. Web. 7 Mar. 2013.A. Koster, Hemmung der cholinesterasen in verscheidenen organen durch eserin, galanthamine und tacrin; conzentrations-wirkungsbeziehungen, bedeuting fir die therapeutisch anwendung. Dissertation 1994; Medezinsiche Fakultat der Humboldt Univ zu Berlin.Abagyan, R., Physical Pharmacology. http://xablab.ucsd.edu/ (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 Acetylcholinesterase Complexed 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." Proc Natl Acad Sci U S A 90.19 (1993): 9031-035. PubMed. Web. 7 Mar. 2013. Kryger, G., et al. "Structure of Acetylcholinesterase Complexed 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. 81-103Sussman, J.. et al. "Atomic Structure of Acetylcholinesterase from Torpedo Californica: A Prototypic Acetylcholine-Binding Protein." Science 253 (1991): 253-61. Sciencemag.org. 21 Dec. 2006. Web. 7 Mar. 2013.