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Identification
Name Tacrine
Accession Number DB00382 (APRD00690)
Type small molecule
Groups approved
Description

A centerally active cholinesterase inhibitor that has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer’s disease and other central nervous system disorders. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Tetrahydroaminacrine
  • Tetrahydroaminoacridine
  • Tetrahydroaminocrin
  • Tetrahydroaminocrine
  • THA
Brand names
  • Cognex
  • Romotal
Brand name mixtures Not Available
Categories
  • Parasympathomimetics
  • Cholinesterase Inhibitors
  • Nootropic Agents
CAS number 321-64-2
Weight Average: 198.2637
Monoisotopic: 198.115698458
Chemical Formula C13H14N2
InChI Key InChIKey=YLJREFDVOIBQDA-UHFFFAOYSA-N
InChI
InChI=1S/C13H14N2/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13/h1,3,5,7H,2,4,6,8H2,(H2,14,15)
Plain Text
IUPAC Name
1,2,3,4-tetrahydroacridin-9-amine
SMILES
NC1=C2CCCCC2=NC2=C1C=CC=C2
Plain Text
Mass Spec show (9.2 KB)
Taxonomy
Kingdom Organic
Classes
  • Acridines
Substructures
  • Acridines
  • Pyridines and Derivatives
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Aminoquinolines and Derivatives
  • Aminopyridines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • (Iso)quinolines and Derivatives
  • Imines
  • Cyclohexenes and Derivatives
Pharmacology
Indication For the palliative treatment of mild to moderate dementia of the Alzheimer's type.
Pharmacodynamics Tacrine is a parasympathomimetic- a reversible cholinesterase inhibitor that is indicated for the treatment of mild to moderate dementia of the Alzheimer's type. 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. Tacrine is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine at cholinergic synapses through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, tacrine's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact. There is no evidence that tacrine alters the course of the underlying dementing process.
Mechanism of action The mechanism of tacrine is not fully known, but it is suggested that the drug is an anticholinesterase agent which reversibly binds with and inactivates cholinesterases. This inhibits the hydrolysis of acetylcholine released from functioning cholinergic neurons, thus leading to an accumulation of acetylcholine at cholinergic synapses. The result is a prolonged effect of acetylcholine.
Absorption Tacrine is rapidly absorbed. Absolute bioavailability of tacrine is approximately 17%.
Volume of distribution
  • 349 ± 193 L
Protein binding 55%
Metabolism

Hepatic. Cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. The major metabolite, 1-hydroxy-tacrine (velnacrine), has central cholinergic activity.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 1A2 1-hydroxytacrine hydroxylation 2.8 0
Route of elimination Not Available
Half life 2 to 4 hours
Clearance Not Available
Toxicity Overdosage with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. The estimated median lethal dose of tacrine following a single oral dose in rats is 40 mg/kg, or approximately 12 times the maximum recommended human dose of 160 mg/day.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Shionogi pharma inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Cognex 10 mg capsule 3.03 USD capsule
Cognex 20 mg capsule 3.03 USD capsule
Cognex 40 mg capsule 3.03 USD capsule
Patents Not Available
Properties
State solid
Melting point 183.5 oC
Experimental Properties
Property Value Source
water solubility 217 mg/L PhysProp
logP 2.2 PhysProp
pKa 9.95 Various sources
Predicted Properties
Property Value Source
water solubility 1.36e-01 g/l ALOGPS
logP 3.13 ALOGPS
logP 2.63 ChemAxon Molconvert
logS -3.16 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 38.91 ChemAxon Molconvert
rotatable bond count 0 ChemAxon Molconvert
refractivity 61.74 ChemAxon Molconvert
polarizability 22.79 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Qizilbash N, Whitehead A, Higgins J, Wilcock G, Schneider L, Farlow M: Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists’ Collaboration. JAMA. 1998 Nov 25;280(20):1777-82. Pubmed
  2. Hansen RA, Gartlehner G, Kaufer DJ, Lohr KN, Carey T: Pubmed
External Links
Resource Link
KEGG Compound C01453 Link_out
PubChem Compound 1935 Link_out
PubChem Substance 46505487 Link_out
ChemSpider 1859 Link_out
BindingDB 8961 Link_out
ChEBI 9389 Link_out
ChEMBL 9389 Link_out
Therapeutic Targets Database DAP000558 Link_out
PharmGKB PA451576 Link_out
HET 760 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic2/tacrine.htm Link_out
Drugs.com http://www.drugs.com/cdi/tacrine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Tacrine Link_out
ATC Codes
  • N06AA18
  • N06DA01
AHFS Codes Not Available
PDB Entries
FDA label Not Available
MSDS show (19.4 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
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. Wang H, Carlier PR, Ho WL, Wu DC, Lee NT, Li CP, Pang YP, Han YF: Effects of bis(7)-tacrine, a novel anti-Alzheimer’s agent, on rat brain AChE. Neuroreport. 1999 Mar 17;10(4):789-93. Pubmed
  3. Traykov L, Tavitian B, Jobert A, Boller F, Forette F, Crouzel C, Di Giamberardino L, Pappata S: In vivo PET study of cerebral [11C] methyl- tetrahydroaminoacridine distribution and kinetics in healthy human subjects. Eur J Neurol. 1999 May;6(3):273-8. Pubmed
  4. Wang H, Tang XC: Anticholinesterase effects of huperzine A, E2020, and tacrine in rats. Zhongguo Yao Li Xue Bao. 1998 Jan;19(1):27-30. Pubmed
  5. 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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Takatori Y: [Mechanisms of neuroprotective effects of therapeutic acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease] Yakugaku Zasshi. 2006 Aug;126(8):607-16. Pubmed
  8. Du DM, Carlier PR: Development of bivalent acetylcholinesterase inhibitors as potential therapeutic drugs for Alzheimer’s disease. Curr Pharm Des. 2004;10(25):3141-56. Pubmed
  9. Krustev AD, Argirova MD, Getova DP, Turiiski VI, Prissadova NA: Calcium-independent tacrine-induced relaxation of rat gastric corpus smooth muscles. Can J Physiol Pharmacol. 2006 Nov;84(11):1133-8. Pubmed
  10. Villarroya M, Garcia AG, Marco JL: New classes of AChE inhibitors with additional pharmacological effects of interest for the treatment of Alzheimer’s disease. Curr Pharm Des. 2004;10(25):3177-84. Pubmed
  11. Marco JL, Carreiras MC: Recent developments in the synthesis of acetylcholinesterase inhibitors. Mini Rev Med Chem. 2003 Sep;3(6):518-24. Pubmed
  12. Ahmed M, Rocha JB, Correa M, Mazzanti CM, Zanin RF, Morsch AL, Morsch VM, Schetinger MR: Inhibition of two different cholinesterases by tacrine. Chem Biol Interact. 2006 Aug 25;162(2):165-71. Epub 2006 Jun 17. Pubmed

2. Cholinesterase

Pharmacological action: yes
Actions: inhibitor

An acylcholine + H(2)O = choline + a carboxylate

Organism class: human
UniProt ID: P06276 Link_out
Gene: BCHE Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wang H, Tang XC: Anticholinesterase effects of huperzine A, E2020, and tacrine in rats. Zhongguo Yao Li Xue Bao. 1998 Jan;19(1):27-30. Pubmed
  2. Krustev AD, Argirova MD, Getova DP, Turiiski VI, Prissadova NA: Calcium-independent tacrine-induced relaxation of rat gastric corpus smooth muscles. Can J Physiol Pharmacol. 2006 Nov;84(11):1133-8. Pubmed
  3. Marco JL, Carreiras MC: Recent developments in the synthesis of acetylcholinesterase inhibitors. Mini Rev Med Chem. 2003 Sep;3(6):518-24. Pubmed
  4. Ahmed M, Rocha JB, Correa M, Mazzanti CM, Zanin RF, Morsch AL, Morsch VM, Schetinger MR: Inhibition of two different cholinesterases by tacrine. Chem Biol Interact. 2006 Aug 25;162(2):165-71. Epub 2006 Jun 17. Pubmed
Enzymes

1. Cytochrome P450 1A2

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. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. Pubmed
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  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
  4. Obach RS, Reed-Hagen AE: Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab Dispos. 2002 Jul;30(7):831-7. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:38

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.