Identification

Name
Tacrine
Accession Number
DB00382  (APRD00690)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
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. Tacrine has been discontinued for the United States market.

Structure
Thumb
Synonyms
  • 1,2,3,4-tetrahydro-9-acridinamine
  • 1,2,3,4-tetrahydro-9-aminoacridine
  • 1,2,3,4-tetrahydroacridin-9-amine
  • 5-amino-6,7,8,9-tetrahydroacridine
  • 9-amino-1,2,3,4-tetrahydroacridine
  • Tacrin
  • Tacrine
  • Tacrinum
  • Tetrahydroaminacrine
  • Tetrahydroaminoacridine
  • THA
External IDs
CI 970
Product Ingredients
IngredientUNIICASInChI Key
Tacrine Hydrochloride4966RNG0BU1684-40-8ZUFVXZVXEJHHBN-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CognexCapsule40 mg/1OralShionogi1993-09-092010-09-30Us
CognexCapsule10 mg/1OralShionogi1993-09-092010-09-30Us
CognexCapsule30 mg/1OralShionogi1993-09-092010-09-30Us
CognexCapsule20 mg/1OralShionogi1993-09-092010-09-30Us
International/Other Brands
Cognex (Shionogi) / Talem (LKM)
Categories
UNII
4VX7YNB537
CAS number
321-64-2
Weight
Average: 198.2637
Monoisotopic: 198.115698458
Chemical Formula
C13H14N2
InChI Key
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)
IUPAC Name
1,2,3,4-tetrahydroacridin-9-amine
SMILES
NC1=C2CCCCC2=NC2=CC=CC=C12

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.

TargetActionsOrganism
AAcetylcholinesterase
inhibitor
Human
ACholinesterase
inhibitor
Human
ULiver carboxylesterase 1Not AvailableHuman
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.

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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when 16-Bromoepiandrosterone is combined with Tacrine.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when 19-norandrostenedione is combined with Tacrine.
5-androstenedioneThe risk or severity of adverse effects can be increased when 5-androstenedione is combined with Tacrine.
AbirateroneThe serum concentration of Tacrine can be increased when it is combined with Abiraterone.
AcebutololTacrine may increase the bradycardic activities of Acebutolol.
AcetaminophenThe serum concentration of Tacrine can be increased when it is combined with Acetaminophen.
AcetylcholineThe risk or severity of adverse effects can be increased when Tacrine is combined with Acetylcholine.
AclidiniumThe therapeutic efficacy of Aclidinium can be decreased when used in combination with Tacrine.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Tacrine.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Tacrine.
Food Interactions
Not Available

References

Synthesis Reference

S. Shirley Yang, Wayne Boisvert, Nouman A. Muhammad, Jay Weiss, "Controlled release tacrine drug delivery systems and methods for preparing same." U.S. Patent US5576022, issued February, 1993.

US5576022
General References
  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:9842955]
  2. Hansen RA, Gartlehner G, Kaufer DJ, Lohr KN, Carey T: Drug Class Review: Alzheimer's Drugs: Final Report [Internet] . [PubMed:20480924]
External Links
Human Metabolome Database
HMDB0014526
KEGG Drug
D08555
KEGG Compound
C01453
PubChem Compound
1935
PubChem Substance
46505487
ChemSpider
1859
BindingDB
8961
ChEBI
45980
ChEMBL
CHEMBL95
Therapeutic Targets Database
DAP000558
PharmGKB
PA451576
HET
THA
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tacrine
ATC Codes
N06DA01 — Tacrine
PDB Entries
1acj / 1mx1 / 2aow / 2aox / 4bds
MSDS
Download (19.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2WithdrawnTreatmentDependence, Cocaine1

Pharmacoeconomics

Manufacturers
  • Shionogi pharma inc
Packagers
  • Sciele Pharma Inc.
  • West-Ward Pharmaceuticals
Dosage forms
FormRouteStrength
CapsuleOral10 mg/1
CapsuleOral20 mg/1
CapsuleOral30 mg/1
CapsuleOral40 mg/1
Prices
Unit descriptionCostUnit
Cognex 10 mg capsule3.03USD capsule
Cognex 20 mg capsule3.03USD capsule
Cognex 40 mg capsule3.03USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)183.5 °CPhysProp
water solubility217 mg/LNot Available
logP2.71HANSCH,C ET AL. (1995)
pKa9.95 (at 20 °C)PERRIN,DD (1972)
Predicted Properties
PropertyValueSource
Water Solubility0.136 mg/mLALOGPS
logP3.13ALOGPS
logP2.63ChemAxon
logS-3.2ALOGPS
pKa (Strongest Basic)8.95ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.91 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity61.74 m3·mol-1ChemAxon
Polarizability22.79 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9783
Blood Brain Barrier+0.978
Caco-2 permeable-0.5267
P-glycoprotein substrateNon-substrate0.6195
P-glycoprotein inhibitor INon-inhibitor0.9247
P-glycoprotein inhibitor IINon-inhibitor0.9103
Renal organic cation transporterNon-inhibitor0.5073
CYP450 2C9 substrateNon-substrate0.8532
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.7248
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5541
Ames testAMES toxic0.9107
CarcinogenicityNon-carcinogens0.9404
BiodegradationNot ready biodegradable0.9773
Rat acute toxicity3.4207 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9351
hERG inhibition (predictor II)Non-inhibitor0.6164
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (9.22 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0002-0900000000-453e4e963f034e9de4cf
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0002-0900000000-256a5702a96325bc74f2
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0002-0900000000-af483bfb98e7e2b87b39
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-006t-0900000000-3c9902ca237f9c26a2fb
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-006x-0900000000-dec59115a19fdec78a9f
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0002-0900000000-c04cbf634e493a774cd5

Taxonomy

Description
This compound belongs to the class of organic compounds known as acridines. These are organic compounds containing the acridine moiety, a linear tricyclic heterocycle which consists of two benzene rings joined by a pyridine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Benzoquinolines
Direct Parent
Acridines
Alternative Parents
4-aminoquinolines / Aminopyridines and derivatives / Benzenoids / Heteroaromatic compounds / Azacyclic compounds / Primary amines / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Acridine / 4-aminoquinoline / Aminoquinoline / Aminopyridine / Benzenoid / Pyridine / Heteroaromatic compound / Azacycle / Organic nitrogen compound / Organopnictogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic amine, acridines (CHEBI:45980) / a small molecule (CPD-10887)

Targets

Details
1. Acetylcholinesterase
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine hydrolase activity
Specific Function
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name
ACHE
Uniprot ID
P22303
Uniprot Name
Acetylcholinesterase
Molecular Weight
67795.525 Da
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:10024872]
  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:10208549]
  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:10210906]
  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:10375753]
  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:10513568]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  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:16880719]
  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:15544504]
  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:17218977]
  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:15544507]
  11. Marco JL, Carreiras MC: Recent developments in the synthesis of acetylcholinesterase inhibitors. Mini Rev Med Chem. 2003 Sep;3(6):518-24. [PubMed:12871155]
  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:16860785]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
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:10375753]
  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:17218977]
  3. Marco JL, Carreiras MC: Recent developments in the synthesis of acetylcholinesterase inhibitors. Mini Rev Med Chem. 2003 Sep;3(6):518-24. [PubMed:12871155]
  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:16860785]
Details
3. Liver carboxylesterase 1
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Triglyceride lipase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR: Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition. Chem Biol. 2003 Apr;10(4):341-9. [PubMed:12725862]

Enzymes

Details
1. Cytochrome P450 1A2
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
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:19754423]
  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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  3. 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:12065442]
  4. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Mohamed LA, Kaddoumi A: Tacrine sinusoidal uptake and biliary excretion in sandwich-cultured primary rat hepatocytes. J Pharm Pharm Sci. 2014;17(3):427-38. [PubMed:25224352]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 16:32