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Identification
Name Donepezil
Accession Number DB00843 (APRD00039)
Type small molecule
Groups approved
Description

Donepezil (Aricept), is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer’s disease where it is used to increase cortical acetylcholine. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, donepezil’s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. Donepezil has been tested in other cognitive disorders including Lewy body dementia and Vascular dementia, but it is not currently approved for these indications. Donepezil has also been studied in patients with Mild Cognitive Impairment, schizophrenia, attention deficit disorder, post-coronary bypass cognitive impairment, cognitive impairment associated with multiple sclerosis, and Down syndrome.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Aricept
  • Aricept ODT
  • Eranz
Brand name mixtures Not Available
Categories
  • Parasympathomimetics
  • Cholinesterase Inhibitors
  • Nootropic Agents
CAS number 120014-06-4
Weight Average: 379.492
Monoisotopic: 379.214743799
Chemical Formula C24H29NO3
InChI Key InChIKey=ADEBPBSSDYVVLD-UHFFFAOYSA-N
InChI
InChI=1S/C24H29NO3/c1-27-22-14-19-13-20(24(26)21(19)15-23(22)28-2)12-17-8-10-25(11-9-17)16-18-6-4-3-5-7-18/h3-7,14-15,17,20H,8-13,16H2,1-2H3
Plain Text
IUPAC Name
2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
SMILES
COC1=CC2=C(C=C1OC)C(=O)C(CC1CCN(CC3=CC=CC=C3)CC1)C2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Indanes
  • Phenols and Derivatives
  • Ethers
  • Catechols
  • Anisoles
  • Benzoyl Derivatives
Substructures
  • Indanes
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Benzoyl Derivatives
  • Phenyl Esters
  • Piperidines
  • Ketones
Pharmacology
Indication For the palliative treatment of mild to moderate dementia of the Alzheimer's type.
Pharmacodynamics Donepezil is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. An early pathophysiological feature of Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, donepezil's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact. There is no evidence that donepezil alters the course of the underlying dementing process.
Mechanism of action Donepezil is a piperidine derivative that is a centerally active, reversible inhibitor of acetylcholinesterase. This drug is structurally unrelated to other anticholinesterase agents. Donepezil's proposed mechanism of action involves the reversible inhibition of cholinesterases (eg. acetylcholinesterase), which prevents the hydrolysis of acetycholine, and leads to an increased concentration of acetylcholine at cholinergic synapses. Evidence suggests that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain.
Absorption Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours.
Volume of distribution
  • 12 L/kg
Protein binding 96%
Metabolism

Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 in the liver and also undergoes glucuronidation. The main metabolite, 6-O-desmethyl donepezil, has been reported to inhibit AChE to the same extent as donepezil in vitro.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 2D6 1-O-desmethyl-donepezil 1-O-demethylation
Cytochrome P450 2D6 6-O-desmethyl-donepezil 6-O-demethylation 0 0
Cytochrome P450 3A4 1-O-desmethyl-donepezil O-demethylation
Cytochrome P450 3A4 6-O-desmethyl-donepezil O-demethylation
Cytochrome P450 3A4 M4 N-dealkylation
Cytochrome P450 2C9 M4 N-dealkylation
Cytochrome P450 2C9 1-O-desmethyl-donepezil 1-O-demethylation
Cytochrome P450 2C9 6-O-desmethyl-donepezil 6-O-demethylation
Route of elimination Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified.
Half life 70 hours
Clearance
  • apparent plasma cl=0.13 L/hr/kg
Toxicity Symptoms of overdose include severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Eisai inc
  • Mutual pharmaceutical co inc
  • Teva pharmaceuticals usa inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Tablet, orally disintegrating Oral
Prices
Unit description Cost Unit
Aricept ODT 30 5 mg Dispersible Tablet Box 272.99 USD box
Aricept 10 mg tablet 10.93 USD tablet
Aricept 5 mg tablet 9.78 USD tablet
Aricept odt 10 mg tablet 8.03 USD tablet
Aricept odt 5 mg tablet 8.03 USD tablet
Patents
Country Patent Number Approved Expires
United States 7727548 2002-06-23 2022-06-23
United States 4895841 1993-11-25 2010-11-25
Canada 2252806 2005-11-22 2017-06-06
Canada 1338808 1996-12-24 2013-12-24
Properties
State solid
Melting point 206.72 oC
Experimental Properties
Property Value Source
water solubility 2.931 mg/L PhysProp
logP 3.6 PhysProp
Predicted Properties
Property Value Source
water solubility 4.50e-03 g/l ALOGPS
logP 4.14 ALOGPS
logP 4.21 ChemAxon Molconvert
logS -4.93 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 38.77 ChemAxon Molconvert
rotatable bond count 6 ChemAxon Molconvert
refractivity 112.11 ChemAxon Molconvert
polarizability 44.34 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Xiong G, Doraiswamy PM: Combination drug therapy for Alzheimer’s disease: what is evidence-based, and what is not? Geriatrics. 2005 Jun;60(6):22-6. Pubmed
  2. Yesavage JA, Mumenthaler MS, Taylor JL, Friedman L, O’Hara R, Sheikh J, Tinklenberg J, Whitehouse PJ: Donepezil and flight simulator performance: effects on retention of complex skills. Neurology. 2002 Jul 9;59(1):123-5. Pubmed
  3. Sugimoto H: Donepezil hydrochloride: a treatment drug for Alzheimer’s disease. Chem Rec. 2001;1(1):63-73. Pubmed
External Links
Resource Link
KEGG Drug D00670 Link_out
PubChem Compound 3152 Link_out
PubChem Substance 46504803 Link_out
ChemSpider 3040 Link_out
BindingDB 8960 Link_out
ChEBI 53289 Link_out
ChEMBL 53289 Link_out
Therapeutic Targets Database DAP000560 Link_out
PharmGKB PA449394 Link_out
Drug Product Database 2232044 Link_out
RxList http://www.rxlist.com/cgi/generic/donepezil.htm Link_out
Drugs.com http://www.drugs.com/cdi/donepezil.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Donepezil Link_out
ATC Codes
  • N06DA02
AHFS Codes
  • 12:04.00
PDB Entries
FDA label show (303.3 KB)
MSDS show (58.2 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
  • Take without regard to meals.
Targets

1. Acetylcholinesterase

Pharmacological action: yes
Actions: inhibitor

Rapidly hydrolyzes choline released into the synapse

Organism class: human
UniProt ID: P22303 Link_out
Gene: ACHE Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Davis KL: Alzheimer’s disease: seeking new ways to preserve brain function. Interview by Alice V. Luddington. Geriatrics. 1999 Feb;54(2):42-7; quiz 48. Pubmed
  2. Kryger G, Silman I, Sussman JL: Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure. 1999 Mar 15;7(3):297-307. Pubmed
  3. Shepherd G, Klein-Schwartz W, Edwards R: Donepezil overdose: a tenfold dosing error. Ann Pharmacother. 1999 Jul-Aug;33(7-8):812-5. Pubmed
  4. Kosasa T, Kuriya Y, Matsui K, Yamanishi Y: Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats. Eur J Pharmacol. 1999 Sep 10;380(2-3):101-7. Pubmed
  5. Jann MW: Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy. 2000 Jan;20(1):1-12. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Sugimoto H: Donepezil hydrochloride: a treatment drug for Alzheimer’s disease. Chem Rec. 2001;1(1):63-73. Pubmed
  8. Ki YS, Park EY, Lee HW, Oh MS, Cho YW, Kwon YK, Moon JH, Lee KT: Donepezil, a potent acetylcholinesterase inhibitor, induces caspase-dependent apoptosis in human promyelocytic leukemia HL-60 cells. Biol Pharm Bull. 2010;33(6):1054-9. Pubmed
  9. Repantis D, Laisney O, Heuser I: Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res. 2010 Jun;61(6):473-81. Epub 2010 Mar 1. Pubmed

2. 5-hydroxytryptamine 2A receptor

Pharmacological action: unknown
Actions: other/unknown

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. This receptor is involved in tracheal smooth muscle contraction, bronchoconstriction, and control of aldosterone production

Organism class: human
UniProt ID: P28223 Link_out
Gene: HTR2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hayslett RL, Tizabi Y: Effects of donepezil, nicotine and haloperidol on the central serotonergic system in mice: implications for Tourette’s syndrome. Pharmacol Biochem Behav. 2005 Aug;81(4):879-86. Pubmed
  2. Hayslett RL, Tizabi Y: Effects of donepezil on DOI-induced head twitch response in mice: implications for Tourette syndrome. Pharmacol Biochem Behav. 2003 Dec;76(3-4):409-15. Pubmed
Enzymes

1. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2C9

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on October 20, 2011 14:43

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.