TACRINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C13H14N2
Molecular Weight	198.2637
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=C2C=CC=CC2=NC3=C1CCCC3

InChI

InChIKey=YLJREFDVOIBQDA-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00382
Curator's Comment: Description was created based on several sources, including https://www.drugs.com/pro/cognex.html

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. 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. is used for the palliative treatment of mild to moderate dementia of the Alzheimer's type. Tacrine was marketed under the trade name Cognex. Because of its liver toxicity and attendant requirement for monitoring liver function, tacrine prescriptions dropped after other acetylcholinesterase inhibitors were introduced, and its use has been largely discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Acetylcholinesterase 209 Target ID: CHEMBL220 Sources: http://www.drugbank.ca/drugs/DB00382	Inhibitor 8504	500.0 nM [IC50]
Butyrylcholinesterase 45 Target ID: CHEMBL1914 Sources: http://www.drugbank.ca/drugs/DB00382	Inhibitor 8504	23.0 nM [IC50]
Histamine N-methyltransferase 10 Target ID: CHEMBL2190 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15834447	Inhibitor 8504	0.46 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Alzheimer’s disease 278 Sources: https://www.drugs.com/pro/cognex.html	Primary		Approved 8583	Cognex Approved Use Cognex® (tacrine hydrochloride capsules) is indicated for the treatment of mild to moderate dementia of the Alzheimer's type. Launch Date 1993

C_max

Value	Dose	Co-administered	Analyte	Population
15.8 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7836549	40 mg single, oral dose: 40 mg route of administration: Oral experiment type: SINGLE co-administered:		TACRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
91.8 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7836549	40 mg single, oral dose: 40 mg route of administration: Oral experiment type: SINGLE co-administered:		TACRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.8 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7836549	40 mg single, oral dose: 40 mg route of administration: Oral experiment type: SINGLE co-administered:		TACRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
160 mg 1 times / day multiple, oral Highest studied dose Dose: 160 mg, 1 times / day Route: oral Route: multiple Dose: 160 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/9236571 https://pubmed.ncbi.nlm.nih.gov/8139083	unhealthy, 71.2 years (range: 52-88 years) Health Status: unhealthy Age Group: 71.2 years (range: 52-88 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/9236571 https://pubmed.ncbi.nlm.nih.gov/8139083	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea (21 patient) Vomiting (21 patient) Anorexia (21 patient) Dyspepsia (21 patient) Diarrhea (21 patient) Abdominal pain (21 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/9236571 https://pubmed.ncbi.nlm.nih.gov/8139083
40 mg 1 times / day multiple, oral Recommended Dose: 40 mg, 1 times / day Route: oral Route: multiple Dose: 40 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020070ap.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020070ap.pdf	Disc. AE: Transaminases increased, Atrial fibrillation... AEs leading to discontinuation/dose reduction: Transaminases increased (1 patient) Atrial fibrillation (1 patient) Dyspnea (1 patient) Chest pain (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020070ap.pdf
80 mg 1 times / day multiple, oral Recommended Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020070ap.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020070ap.pdf	Disc. AE: Transaminases increased, Nausea... AEs leading to discontinuation/dose reduction: Transaminases increased (1 patient) Nausea (1 patient) Vomiting (1 patient) Pallor (1 patient) Vasodilatation (1 patient) Sweating increased (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020070ap.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP1A2 1197 OCT1 393 OCT3 92 OCTN2 59 P-gp 2052

Drug as victim

Target	Modality	Activity
P-gp 2052	substrate 4014 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928264/	inconclusive
CYP1A2 1197	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/16128907/;https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014350/	yes
OCT1 393	substrate 4014 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928264/	yes
OCT3 92	substrate 4014 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928264/	yes
OCTN2 59	substrate 4014 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928264/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://academic.oup.com/toxsci/article-pdf/136/2/581/16686164/kft205.pdf

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45980	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45980
ChemicalBook	CB7699634	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7699634
eMolecules	872890	https://www.emolecules.com/cgi-bin/more?vid=872890
MolPort	MolPort-000-881-472	https://www.molport.com/shop/molecule-link/MolPort-000-881-472
ZINC	ZINC000019014866	http://zinc15.docking.org/substances/ZINC000019014866

PubMed

Title	Date	PubMed
An appraisal of tacrine-extended suxamethonium.	1970 Feb	5443962
Ketamine-induced postanesthetic delirium attenuated by tetrahydroaminoacridine.	1974 Jul	4857761
Suxamethonium apnoea masked by tetrahydroaminacrine.	1978 Jul-Aug	686334
Amino acridines action on Friend's retrovirus in relation to their molecular ionization.	1989	2790144
Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes.	1989 Nov 28	2606156
A comparison of the effects of cholinergic and dopaminergic agents on scopolamine-induced hyperactivity in mice.	1990 Nov	2243341
Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.	1992 Mar 20	1552502
Tacrine inhibits ventricular fibrillation induced by ischaemia and reperfusion and widens QT interval in rat.	1993 Mar	8490946
Antiamnesic and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats.	1993 Nov 30	8119309
Severe parkinsonian symptom development on combination treatment with tacrine and haloperidol.	1995 Aug	7593712
Systemic administration of lithium chloride and tacrine but not kainic acid augments citrulline content of rat brain.	1995 Dec 27	8788450
Delirium caused by tacrine and ibuprofen interaction.	1996 Jun	8633709
Convulsive effects of tacrine.	1996 May 11	8622541
Adverse interaction of tacrine and haloperidol.	1996 Nov	8890692
Therapeutic approaches to age-associated neurocognitive disorders.	2001 Sep	22033831
Comparative effect of Prunus persica L. BATSCH-water extract and tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) on concentration of extracellular acetylcholine in the rat hippocampus.	2003 Aug	12860300
Validation of the tremulous jaw movement model for assessment of the motor effects of typical and atypical antipychotics: effects of pimozide (Orap) in rats.	2005 Feb	15680188
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Evidence for the involvement of central serotonergic mechanisms in cholinergic tremor induced by tacrine in Balb/c mice.	2005 Sep 8	15990178
Pharmacological characterization of orally active cholinesterase inhibitory activity of Prunus persica L. Batsch in rats.	2006	16954599
In vitro and in vivo characterization of F-97013-GD, a partial 5-HT1A agonist with antipsychotic- and antiparkinsonian-like properties.	2006 Jul	16643965
	2006 Jun	20480924
Long-term tetrahydroaminoacridine treatment and quantitative EEG in Alzheimer's disease.	2007	17982896
WITHDRAWN: Tacrine for Alzheimer's disease.	2007 Jul 18	17636619
Allosteric modulation of muscarinic acetylcholine receptors.	2007 Sep	19305798
Effects of zonisamide on experimental tremors in rats.	2008	17587636
The investigation of structure-activity relationships of tacrine analogues: electronic-topological method.	2008 Aug 6	19662147
NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity.	2008 Dec 25	19053746
Dose-related effects of the acetylcholinesterase inhibitor tacrine on cocaine and food self-administration in rats.	2008 Jan	17917719
1-Phenyl-6,7,8,9-hexa-hydro-1H,5H-cyclo-hepta-[1',2':2,3]pyrido[6,5-c]pyrazol-4-amine: a new tacrine analogue.	2008 May 10	21202575
New performance of biosensor technology for Alzheimer's disease drugs: in vitro comparison of tacrine and 7-methoxytacrine.	2008 Oct	18987590
The 5-choice continuous performance test: evidence for a translational test of vigilance for mice.	2009	19156216
Cholinergic influence on memory stages: A study on scopolamine amnesic mice.	2009 Aug	20523872
Rapid determination of tacrine and other drug metabolites in microsomal incubate by newly developed targeting algorithm on UHPLC/TOFMS.	2009 Dec 15	19932643
Once-daily transdermal rivastigmine in the treatment of Alzheimer's disease.	2009 Feb 6	19920911
Identification of FDA-approved drugs and bioactives that protect hair cells in the zebrafish (Danio rerio) lateral line and mouse (Mus musculus) utricle.	2009 Jun	19241104
Coupling an HCN2-expressing cell to a myocyte creates a two-cell pacing unit.	2009 Nov 1	19736302
Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging.	2010	20552041
Tacrine-NO donor and tacrine-ferulic acid hybrid molecules as new anti-Alzheimer agents: hepatotoxicity and influence on the cytochrome P450 system in comparison to tacrine.	2010	20533758
A second-generation device for automated training and quantitative behavior analyses of molecularly-tractable model organisms.	2010 Dec 17	21179424
Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones.	2010 Feb	19954865
Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis.	2010 Jan 12	20068258
A novel animal model to evaluate the ability of a drug delivery system to promote the passage through the BBB.	2010 Jan 18	19944736
Dual-acting drugs: an in vitro study of nonimidazole histamine H3 receptor antagonists combining anticholinesterase activity.	2010 Jul 5	20512794
Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation.	2011 Aug	21540358
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors.	2013 Mar 25	23123248
A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans.	2014 Jan	24085192
N-palmitoyl serotonin alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of BDNF and p-CREB in mice.	2015 Dec 5	26408985

Patents

Sample Use Guides

In Vivo Use Guide

Oral Initially, 10 mg 4 times daily for at least 4 weeks. If well tolerated and increased serum ALT concentrations have not occurred, increase dosage to 20 mg 4 times daily; if tolerated, increase dosage in 40-mg daily increments (divided into 4 doses daily) at 4-week intervals up to a maximum of 160 mg daily (40 mg 4 times daily).

Route of Administration: Oral

In Vitro Use Guide

Tacrine (0.01-10 uM) inhibited both human and rat HNMT activity in a concentration-dependent manner, but was less potent on both human embryonic kidney and recombinant human brain HNMT than on rat kidney HNMT (IC50 values were 0.46 and 0.70 uM vs. 0.29 uM, respectively).

Name

Type

Language

TACRINAL

Preferred Name

English

TACRINE

Official Name

English

Tacrine [WHO-DD]

Common Name

English

TACRINE [VANDF]

Common Name

English

tacrine [INN]

Common Name

English

TACRINE [MI]

Common Name

English

9-AMINO-1,2,3,4-TETRAHYDROACRIDINE

Systematic Name

English

Classification Tree Code System Code

WHO-ATC

N06DA01