Acetylcholinesterase Inhibitors for Alzheimer’s disease: Past, Present, and Potential Future

Main Article Content

Brandon Truong Jose Paredes Quiroz Ronny Priefer

Abstract

Alzheimer’s Diseases (AD) is a neurodegenerative disorder characterized by progressive neuronal loss leading to cognitive decline. Although there is yet to be a cure nor a way to reverse the neuronal damage, there are current treatments to amend some of the cognitive symptoms associated with AD. Acetylcholinesterase inhibitors (AChEi) are the primary agents of choice and have had profound implications throughout the past decades. AChEi such as donepezil, rivastigmine, and galantamine mediates and increases cholinergic activities in the central nervous system (CNS), and have been shown to improve and preserve cognition in AD patients. Beyond the current drugs on the market, investigational discoveries continue to explore the potential of safer and more efficacious AChEi agents for the treatment of AD. There have been quite a few challenges, given the high failure rates. Yet, these very trials and studies have been a fundamental step towards better understanding the treatments of AD and have provided some insight on the potential to surpass what is currently available.  

Article Details

How to Cite
TRUONG, Brandon; QUIROZ, Jose Paredes; PRIEFER, Ronny. Acetylcholinesterase Inhibitors for Alzheimer’s disease: Past, Present, and Potential Future. Medical Research Archives, [S.l.], v. 8, n. 12, dec. 2020. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2271>. Date accessed: 24 jan. 2021. doi: https://doi.org/10.18103/mra.v8i12.2271.
Section
Research Articles

References

1. DeTure, M.A., Dickson, D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegeneration 14, 32 (2019). https://doi.org/10.1186/s13024-019-0333-5
2. 2020 Alzheimer's disease facts and figures. Alzheimer's Dement., 16 (2020) 391-460. https://doi.org/10.1002/alz.12068
3. Ballard, C, et al. Alzheimer's disease. The Lancet. 377 (2011) 1019-103. https://doi.org/10.1016/S0140-6736(10)61349-9
4. Center for Disease Control and Prevention (CDC) Alzhimer’s disease and related dementias. https://www.cdc.gov/aging/aginginfo/alzheimers.htm
5. Death Count Continues to Grow in Nursing Homes and Assisted Living Communities, Alzheimer’s Association Calls for Action. Alzheimer's Association. May 11, 2020 https://www.alz.org/news/2020/death-count-continues-to-grow-in-nursing-homes-and
6. Perl DP. Neuropathology of Alzheimer's disease. Mt Sinai J Med. 2010 Jan-Feb;77(1):32-42. doi: 10.1002/msj.20157. PMID: 20101720; PMCID: PMC2918894.
7. Qaseem A, Snow V, Cross JT Jr, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Annals of Internal Medicine. 2008 Mar;148(5):370-378. DOI: 10.7326/0003-4819-148-5-200803040-00008.
8. Rabins P.V. et al. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients with Alzheimer's Disease and Other Dementias. Focus (Am Psychiatr Publ). 15,1 (2017) 110-128. https://doi.org/10.1176/appi.focus.15106
9. Exelon (rivastigmine transdermal patch) package insert. East Hanover, NJ: Novartis Pharmaceutical Corporation https://www.novartis.us/sites/www.novartis.us/files/exelonpatch.pdf
10. Razadyne, Razadyne ER (galantamine) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2015 Feb Reference ID: 3699683 https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021615s021lbl.pdf
11. Aricept (donepezil hydrochloride) package insert. Woodcliff Lake, NJ: Eisai Co., Ltd.; 2017 March. Reference ID: 3096907 https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020690s035,021720s008,022568s005lbl.pdf
12. Namzaric (memantine and donepezil hydrochloride) extended-release capsules package insert. Parsippany, NJ; Actavis-US: 2016 Jul. Reference ID: 3960310 https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206439s003lbl.pdf
13. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137-47. doi: 10.1136/jnnp.66.2.137. PMID: 10071091; PMCID: PMC1736202.
14. Atropine Sulfate Injection packet insert. Lake Zurich, IL Fresenius Kabi USA;. 2018 Jan Reference ID: 4213166 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209260s000lbl.pdf
15. Ditropan XL (oxybutynin chloride) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2016 Sept https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020897s035lbl.pdf
16. Gray SL, Anderson ML, Dublin S., et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663
17. Campbell N., et al., The cognitive impact of anticholinergics: A clinical review. Clin Interv Aging 4 (2009) 225-233 doi:10.2147/cia.s5358
18. The American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc (2019) 1-21. https://qioprogram.org/sites/default/files/2019BeersCriteria_JAGS.pdf
19. Nordberg A, Darreh-Shori T, Peskind E, et al. Different cholinesterase inhibitor effects on CSF cholinesterases in Alzheimer patients. Curr Alzheimer Res. 2009;6(1):4-14. doi:10.2174/156720509787313961
20. Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 2013;11(3):315-335. doi:10.2174/1570159X11311030006
21. Qaseem A, Snow V, Cross JT Jr, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148(5):370-378. doi:10.7326/0003-4819-148-5-200803040-00008
22. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(3):126-135. doi:10.1212/WNL.0000000000004826
23. Agboton C, et al., Impact of nighttime donepezil administration on sleep in the older adult population: A retrospective study Mental Health Clinician 4,5 (2014) 257-259 https://doi.org/10.9740/mhc.n222761
24. Bentué-Ferrer D., Tribut O., Polard, E. et al. Clinically Significant Drug Interactions with Cholinesterase Inhibitors. CNS Drugs 17, 947–963 (2003). https://doi.org/10.2165/00023210-200317130-00002
25. Finley R. Tacrine for Alzheimer’s Disease: Therapeutic Considerations. Journal of Pharmacy Practice. 1995;8(5):217-227. doi:10.1177/089719009500800505
26. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Tacrine. [Updated 2020 Jan 15]. https://www.ncbi.nlm.nih.gov/books/NBK547868/
27. Cognex (tacrine) Center for drug evaluation and research approval package. Detroit, MI; Parke-Davis Pharmaceutical, Inc.; 1997 Oct. https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020070ap.pdf
28. Cognex (tacrine) package insert. Atlanta, GA; Sciele Pharmac, Inc.; 2008 Aug.
29. Davis KL, Powchik P. Tacrine. Lancet. 1995 Mar 11;345(8950):625-30. doi: 10.1016/s0140-6736(95)90526-x. PMID: 7534856.
30. Harel M, Schalk I, Ehret-Sabatier L, et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci U S A. 1993;90(19):9031-9035. doi:10.1073/pnas.90.19.9031
31. Ogura H, Kosasa T, Kuriya Y, Yamanishi Y. Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro. Methods Find Exp Clin Pharmacol. 2000 Oct;22(8):609-13. doi: 10.1358/mf.2000.22.8.701373. PMID: 11256231.
32. Junaid M, Islam N, Hossain MK, Ullah MO, Halim MA (2019) Metal based donepezil analogues designed to inhibit human acetylcholinesterase for Alzheimer’s disease. PLOS ONE 14(2): e0211935. https://doi.org/10.1371/journal.pone.0211935
33. Fuentes AV, Pineda MD, Venkata KCN. Comprehension of Top 200 Prescribed Drugs in the US as a Resource for Pharmacy Teaching, Training and Practice. Pharmacy (Basel). 2018;6(2):43. Published 2018 May 14. doi:10.3390/pharmacy6020043
34. Vogel S.M, Mican L.M, Smith T.L. Donepezil-induced QTc prolongation: A case report. Ment Health Clin. 9,3 (2019) 128-132. doi:10.9740/mhc.2019.05.128
35. Sadowsky C, et al. Switching from oral cholinesterase inhibitors to the rivastigmine transdermal patch. CNS Neurosci Ther. 16,1 (2010) 51-60. doi:10.1111/j.1755-5949.2009.00119.x
36. Exelon (rivastigmine) capsule package insert. East Hanover, NJ: Novartis Pharmaceutical Corporation 2015 Jan.
37. Emre M, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 351 (2004) :2509-2518, doi: 10.1056/NEJMoa041470
38. Eldufani J, Blaise G. The role of acetylcholinesterase inhibitors such as neostigmine and rivastigmine on chronic pain and cognitive function in aging: A review of recent clinical applications. Alzheimers Dement (N Y). 2019;5:175-183. Published 2019 Jun 4. doi:10.1016/j.trci.2019.03.004
39. Jann M.W. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy. 20,1 (2000) 1-12. doi:10.1592/phco.20.1.1.3466
40. Aronson S, Van Baelen B, Kavanagh S, Schwalen S. Optimal dosing of galantamine in patients with mild or moderate Alzheimer's disease: post Hoc analysis of a randomized, double-blind, placebo-controlled trial. Drugs Aging. 2009;26(3):231-9. doi: 10.2165/00002512-200926030-00004. PMID: 19358618.
41. Huang F, Fu Y. A review of clinical pharmacokinetics and pharmacodynamics of galantamine, a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, in healthy subjects and patients. Curr Clin Pharmacol. 5,2 (2010) 115-124. doi:10.2174/157488410791110805
42. Cheung J, et al. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem. 55,22 2012 10282-10286. doi:10.1021/jm300871x
43. Woodruff-Pak D.S, et al. Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci U S A. 98,4 (2001) 2089-2094. doi:10.1073/pnas.031584398
44. Harry M. Greenblatt, Catherine Guillou, Daniel Guénard, Anat Argaman, Simone Botti, Bernard Badet, Claude Thal, Israel Silman, and Joel L. Sussman. Journal of the American Chemical Society 2004 126 (47), 15405-15411 doi: 10.1021/ja0466154
45. Birks J, Wilcock GG. Velnacrine for Alzheimer's disease. Cochrane Database Syst Rev. 2004;(2):CD004748. doi: 10.1002/14651858.CD004748. PMID: 15106259.
46. Zemlan F.P, et al., double-blind placebo-controlled study of velnacrine in alzheimer disease. Life Sciences 58,21 (1996) 1823-1832
47. Tabarrini O, et al. Velnacrine Thiaanalogues as Potential Agents for Treating Alzheimer’s Disease Bioorganic & Medicinal Chemistry 9 (2001) 2921–2928 https://doi.org/10.1016/S0968-0896(01)00171-7
48. National Center for Biotechnology Information. PubChem Compound Summary for CID 3655, Velnacrine. https://pubchem.ncbi.nlm.nih.gov/compound/Velnacrine
49. Skibiński, R, et al., Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors. Chem Biol Drug Des. 91 (2018) 505–518
50. Xiao S, et al., Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild-tomoderate Alzheimer’s disease: a Phase II multicenter randomised controlled trial. Age and Ageing 46 (2017) 767–773, https://doi.org/10.1093/ageing/afx045
51. Coelho Filho JMJMC, Birks J. Physostigmine for dementia due to Alzheimer's disease. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD001499. DOI: 10.1002/14651858.CD001499.
52. Physostigmine package insert. Bad Homburg, Germany. Fresenius Kabi Pharmaceutical 2018 Jan.
53. Möller H-J, Hampel H, Hegerl U, Schmitt W, Walter K. Double-blind, randomized, placebo-controlled clinical trial on the efficacy and tolerability of a physostigmine patch in patients with senile dementia of the Alzheimer type. Pharmacopsychiatry. 1999 May;32(3):99-106. doi: 10.1055/s-2007-979202. PMID: 10463377.
54. Imbimbo BP, Martelli P, Troetel WM, Lucchelli F, Lucca U, Thal LJ. Efficacy and safety of eptastigmine for the treatment of patients with Alzheimer's disease. Neurology. 1999 Mar 10;52(4):700-8. doi: 10.1212/wnl.52.4.700. PMID: 10078713.
55. Braida D, Sala M. Eptastigmine: ten years of pharmacology, toxicology, pharmacokinetic, and clinical studies. CNS Drug Rev. 2001;7(4):369-386. doi:10.1111/j.1527-3458.2001.tb00205.x
56. Winblad B, et al., Phenserine Efficacy in Alzheimer’s diseaseAlzheimers Dis. 22,4 (2010) 1201–1208. doi:10.3233/JAD-2010-101311.
57. Mikkilineni, Sohan et al. “The anticholinesterase phenserine and its enantiomer posiphen as 5'untranslated-region-directed translation blockers of the Parkinson's alpha synuclein expression.” Parkinson's disease 2012 (2012): 142372. doi:10.1155/2012/142372
58. Wang Y, Sun Y, Guo Y, Wang Z, Huang L, Li X. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. J Enzyme Inhib Med Chem. 2016;31(3):389-97. doi: 10.3109/14756366.2015.1024675. Epub 2015 Mar 23. PMID: 25798687.
59. Alix F, et al., Dihydroquinoline Carbamate DQS1-02 as a Prodrug of a Potent Acetylcholinesterase Inhibitor for Alzheimer’s Disease Therapy: Multigram-Scale Synthesis, Mechanism Investigations, in Vitro Safety Pharmacology, and Preliminary in Vivo Toxicology Profile. ACS Omega 3,12 (2018) 18387-18397 doi:10.1021/acsomega.8b02121
60. Smith C, et al., Pharmacological Activity and Safety Profile of P10358, a Novel, Orally Active Acetylcholinesterase Inhibitor for Alzheimer’s Disease Journal of Pharmacology and Experimental Therapeutics 280,2 (1997) 710 –720. https://jpet.aspetjournals.org/content/280/2/710.short
61. Trabace L, Cassano T, Loverre A, Steardo L, Cuomo V. CHF2819: pharmacological profile of a novel acetylcholinesterase inhibitor. CNS Drug Rev. 2002;8(1):53-69. doi:10.1111/j.1527-3458.2002.tb00215.x
62. Trabace L, et al., Biochemical and Neurobehavioral Profile of CHF2819, a Novel, Orally Active Acetylcholinesterase Inhibitor for Alzheimer’s Disease. Journal of Pharmacology and Experimental Therapeutics 294,1 (2000) 187-194. PMID: 10871311. https://pubmed.ncbi.nlm.nih.gov/10871311/
63. Baakman AC, 't Hart E, Kay DG, et al. First in human study with a prodrug of galantamine: Improved benefit-risk ratio?. Alzheimers Dement (N Y). 2016;2(1):13-22. Published 2016 Jan 20. doi:10.1016/j.trci.2015.12.003
64. Stavrakov G, et al., Docking-based design and synthesis of galantamine–camphane hybrids as inhibitors of acetylcholinesterase. Chem Biol Drug Des. 90 (2017) 709-718 https://doi.org/10.1111/cbdd.12991
65. Nam SO, Park DH, Lee YH, Ryu JH, Lee YS. Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem. 2014 Feb 15;22(4):1262-7. doi: 10.1016/j.bmc.2014.01.010. Epub 2014 Jan 11. PMID: 24485122
66. Yang J, et al., Synthesis and biological evaluation of 3-arylbenzofuranone derivatives as potential anti-Alzheimer’s disease agents. Journal of Enzyme Inhibition and Medicinal Chemistry 35,1 2020 804-814 https://doi.org/10.1080/14756366.2020.1740694
67. Ringman JM, Cummings JL. Metrifonate (Trichlorfon): a review of the pharmacology, pharmacokinetics and clinical experience with a new acetylcholinesterase inhibitor for Alzheimer's disease. Expert Opin Investig Drugs. 1999 Apr;8(4):463-71. doi: 10.1517/13543784.8.4.463. PMID: 15992092.
68. López-Arrieta JM, Schneider L. Metrifonate for Alzheimer's disease. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003155. doi: 10.1002/14651858.CD003155.pub3. PMID: 16625573.
69. Shaikha S, et al., Design, synthesis and evaluation of pyrazole bearing α-aminophosphonate derivatives as potential acetylcholinesterase inhibitors against Alzheimer’s disease. Bioorganic Chemistry 96 (2020) 103589 https://doi.org/10.1016/j.bioorg.2020.103589
70. Neto D, et al., A new guanylhydrazone derivative as a potential acetylcholinesterase inhibitor for Alzheimer's disease: synthesis, molecular docking, biological evaluation and kinetic studies by nuclear magnetic resonance. RSC Adv., 7 (2017) 33944 https://doi.org/10.1039/C7RA04180B
71. Fernandes T, et al., Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer’s Disease Arch. Pharm. Chem. Life Sci. e1700163 (2017) 350 doi: 10.1002/ardp.201700163
72. Lolaka N, et al., Sulphonamides incorporating 1,3,5-triazine structural motifs show antioxidant, acetylcholinesterase, butyrylcholinesterase, and tyrosinase inhibitory profile. Journal of Enzyme Inhibition and Medicinal Chemistry 35,1 (2020) 424-435 https://doi.org/10.1080/14756366.2019.1707196
73. Mo J, Chen T, Yang H, et al. Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease. J Enzyme Inhib Med Chem. 2020;35(1):330-343. doi:10.1080/14756366.2019.1699553
74. Yang G, et al., Huperzine A for Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. A Systematic Review and Meta-Analysis of Randomized Clinical Trials. PLoS ONE 8,9 2013) doi:10.1371/journal.pone.0074916
75. Rafii S, et al. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology.76,16 (2011) 1389-1394. doi:10.1212/WNL.0b013e318216eb7b
76. Jia JY, Zhao QH, Liu Y, Gui YZ, et al. Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease. Acta Pharmacol Sin. 2013 Jul;34(7):976-82. doi: 10.1038/aps.2013.7. Epub 2013 Apr 29. PMID: 23624756; PMCID: PMC4002618.
77. Ali S, et al., Kinetics and molecular docking of vasicine from Adhatoda vasica: An acetylcholinesterase inhibitor for Alzheimer's disease. South African Journal of Botany 104 (2016) 118-124 doi:10.1016/j.sajb.2015.09.021
78. Seidl C, Correia BL, Stinghen AE, Santos CA. Acetylcholinesterase inhibitory activity of uleine from Himatanthus lancifolius. Z Naturforsch C J Biosci. 2010 Jul-Aug;65(7-8):440-4. doi: 10.1515/znc-2010-7-804. PMID: 20737911.
79. Perry NS, Bollen C, Perry EK, Ballard C. Salvia for dementia therapy: review of pharmacological activity and pilot tolerability clinical trial. Pharmacol Biochem Behav. 2003 Jun;75(3):651-9. doi: 10.1016/s0091-3057(03)00108-4. PMID: 12895683.
80. Jiang Y, Gao H, Turdu G. Traditional Chinese medicinal herbs as potential AChE inhibitors for anti-Alzheimer's disease: A review. Bioorg Chem. 2017 Dec;75:50-61. doi: 10.1016/j.bioorg.2017.09.004. Epub 2017 Sep 6. PMID: 28915465.
81. Deng X, et al., Polygala tenuifolia: a source for anti-Alzheimer’s disease drugs Pharmaceutical Biology 58,1 (2020) 410-416. doi: 10.1080/13880209.2020.1758732. PMID: 32429787; PMCID: PMC7301717.
82. Choi YT, et all. The green tea polyphenol (-)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci. 2001 Dec 21;70(5):603-14. doi: 10.1016/s0024-3205(01)01438-2. PMID: 11811904.

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