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| 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. |
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| Structure |
Download: MOL | SDF | SMILES | InChI Display: 2D Structure | 3D Structure |
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| Synonyms | Not Available | |||||||||||||||||||||||||||||||||||||||||||||
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| Brand name mixtures | Not Available | |||||||||||||||||||||||||||||||||||||||||||||
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| CAS number | 120014-06-4 | |||||||||||||||||||||||||||||||||||||||||||||
| Weight |
Average: 379.492 Monoisotopic: 379.214743799 |
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| 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
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| IUPAC Name |
2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
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| SMILES |
COC1=CC2=C(C=C1OC)C(=O)C(CC1CCN(CC3=CC=CC=C3)CC1)C2
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| Mass Spec | Not Available | |||||||||||||||||||||||||||||||||||||||||||||
| Taxonomy | ||||||||||||||||||||||||||||||||||||||||||||||
| Kingdom | Organic | |||||||||||||||||||||||||||||||||||||||||||||
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| 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. | |||||||||||||||||||||||||||||||||||||||||||||
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| 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.
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| 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 | |||||||||||||||||||||||||||||||||||||||||||||
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| 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. | |||||||||||||||||||||||||||||||||||||||||||||
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| Pathways | Not Available | |||||||||||||||||||||||||||||||||||||||||||||
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| Properties | ||||||||||||||||||||||||||||||||||||||||||||||
| State | solid | |||||||||||||||||||||||||||||||||||||||||||||
| Melting point | 206.72 oC | |||||||||||||||||||||||||||||||||||||||||||||
| Experimental Properties |
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| Synthesis Reference | Not Available | |||||||||||||||||||||||||||||||||||||||||||||
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| FDA label | show (303.3 KB) | |||||||||||||||||||||||||||||||||||||||||||||
| MSDS | show (58.2 KB) | |||||||||||||||||||||||||||||||||||||||||||||
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| Drug Interactions | Not Available | |||||||||||||||||||||||||||||||||||||||||||||
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| Targets |
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Pharmacological action: yes
Actions: inhibitor Rapidly hydrolyzes choline released into the synapse Organism class: humanUniProt ID: P22303 ![]() Gene: ACHE ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
2. 5-hydroxytryptamine 2A receptor Pharmacological action: unknownActions: 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: humanUniProt ID: P28223 ![]() Gene: HTR2A ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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| Enzymes |
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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![]() Gene: CYP2D6 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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![]() Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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![]() Gene: CYP2C9 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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| Comments |
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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.