DrugBank: Benztropine (DB00245)

targets (3) enzymes (2)

Identification

Name

Benztropine

Accession Number

DB00245 (APRD00748)

Type

small molecule

Groups

approved

Description

Benzotropine is a centrally-acting, antimuscarinic agent used as an adjunct in the treatment of Parkinson’s disease. It may also be used to treat extrapyramidal reactions, such as dystonia and Parkinsonism, caused by antipsychotics (e.g. phenothiazines). Symptoms of Parkinson’s disease and extrapyramidal reactions arise from decreases in dopaminergic activity which creates an imbalance between dopaminergic and cholinergic activity. Anticholinergic therapy is thought to aid in restoring this balance leading to relief of symptoms. In addition to its anticholinergic effects, benztropine also inhibits the reuptake of dopamine at nerve terminals via the dopamine transporter. Benzotropine also produces antagonistic effects at the histamine H1 receptor.

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Benzatropina [INN-Spanish]
Benzatropine
Benzatropine mesilate
Benzatropinum [INN-Latin]
Benztropine Mesylate
Benztropinum
Tropine Benzohydryl Ether

Brand names

Akitan
Apo-Benztropine (Apotex)
Cobrentin
Cogentin (Merck Frosst)
Cogentinol (Astra (Germany, discontinued))
PMS Benztropine (Pharmascience)

Brand name mixtures

Not Available

Categories

Antiparkinson Agents
Antidyskinetics
Muscarinic Antagonists
Parasympatholytics

CAS number

86-13-5

Weight

Average: 307.4293
Monoisotopic: 307.193614427

Chemical Formula

C₂₁H₂₅NO

InChI Key

InChIKey=GIJXKZJWITVLHI-RTBURBONSA-N

InChI

InChI=1S/C21H25NO/c1-22-18-12-13-19(22)15-20(14-18)23-21(16-8-4-2-5-9-16)17-10-6-3-7-11-17/h2-11,18-21H,12-15H2,1H3/t18-,19-/m1/s1

Plain Text

IUPAC Name

(1R,5R)-3-(diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]octane

SMILES

[H][C@@]12CC[C@]([H])(CC(C1)OC(C1=CC=CC=C1)C1=CC=CC=C1)N2C

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Diphenylmethanes

Substructures

Benzyl Alcohols and Derivatives
Pyrrolidines
Ethers
Benzene and Derivatives
Aliphatic and Aryl Amines
Diphenylmethanes
Heterocyclic compounds
Aromatic compounds
Tropanes
Alkaloids and Alkaloid Derivatives
Piperidines

Pharmacology

Indication

For use as an adjunct in the therapy of all forms of parkinsonism and also for use in the control of extrapyramidal disorders due to neuroleptic drugs.

Pharmacodynamics

Benztropine is an anticholinergic used in the symptomatic treatment of all etiologic groups of parkinsonism and drug-induced extrapyramidal reactions (except tardive dyskinesia). Benztropine possesses both anticholinergic and antihistaminic effects, although only the former has been established as therapeutically significant in the management of parkinsonism. Benztropine's anticholinergic activity is about equal to that of atropine. Benztropine also inhibits dopamine reuptake via the dopamine transporter at nerve terminals.

Mechanism of action

Benztropine is a selective M1 muscarinic acetylcholine receptor antagonist. It is able to discriminate between the M1 (cortical or neuronal) and the peripheral muscarinic subtypes (cardiac and glandular). Benztropine partially blocks cholinergic activity in the CNS, which is responsible for the symptoms of Parkinson's disease. It is also thought to increase the availability of dopamine, a brain chemical that is critical in the initiation and smooth control of voluntary muscle movement.

Absorption

Onset of action is 1-2 hours following oral administration. The onset of action is within minutes when administered by IM or IV injection.

Volume of distribution

Not Available

Protein binding

~95% to serum proteins

Metabolism

Route of elimination

Not Available

Half life

Not Available

Clearance

Not Available

Toxicity

Signs of overdose include confusion, nervousness, listlessness, hallucinations, dizziness; muscle weakness, ataxia, dry mouth, mydriasis, blurred vision, palpitations, tachycardia, elevated blood pressure, nausea, vomiting, dysuria, numbness of fingers, headache, delirium, coma, shock, convulsions, respiratory arrest, anhidrosis, hyperthermia, glaucoma, and constipation.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Hikma farmaceutica (portugal) sa
Nexus pharmaceuticals inc
Pharmaforce inc
Lundbeck inc
Actavis totowa llc
Corepharma llc
Invagen pharmaceuticals inc
Lannett holdings inc
Mutual pharmaceutical co inc
Pliva inc
Quantum pharmics ltd
Usl pharma inc
Vintage pharmaceuticals llc
Merck and co inc

Packagers

Advanced Pharmaceutical Services Inc.
Amerisource Health Services Corp.
Amneal Pharmaceuticals
AQ Pharmaceuticals Inc.
Cardinal Health
Comprehensive Consultant Services Inc.
Corepharma LLC
Coupler Enterprises Inc.
Dept Health Central Pharmacy
Direct Dispensing Inc.
Dispensing Solutions
Goldline Laboratories Inc.
Heartland Repack Services LLC
Hikma Pharmaceuticals
Ivax Pharmaceuticals
Liberty Pharmaceuticals
Lundbeck Inc.
Major Pharmaceuticals
Medisca Inc.
Merck & Co.
Murfreesboro Pharmaceutical Nursing Supply
Neuman Distributors Inc.
Nexus Pharmaceuticals
Nucare Pharmaceuticals Inc.
PCA LLC
Pharmaceutical Packaging Center
Pharmedix
Physicians Total Care Inc.
Pliva Inc.
Prepackage Specialists
Prepak Systems Inc.
Qualitest
Rebel Distributors Corp.
Remedy Repack
Rising Pharmaceuticals
Sandhills Packaging Inc.
Schein Pharmaceutical Inc.
Southwood Pharmaceuticals
Tya Pharmaceuticals
UDL Laboratories
United Research Laboratories Inc.
USL Pharma Inc.
Vangard Labs Inc.
Vintage Pharmaceuticals Inc.
West-Ward Pharmaceuticals

Dosage forms

Form	Route	Strength
Injection	Intramuscular	1 mg/ml
Injection	Intravenous	1 mg/ml
Tablet	Oral	0.5 mg
Tablet	Oral	1 mg
Tablet	Oral	2 mg

Prices

Unit description	Cost	Unit
Cogentin 2 mg/2 ml ampule	70.09 USD	ml
Benztropine 2 mg/2 ml ampule	37.5 USD	ml
Benztropine 2 mg/2 ml vial	33.0 USD	ml
Benztropine mesylate powder	26.38 USD	g
Benztropine mes 2 mg tablet	0.41 USD	tablet
Benztropine mes 1 mg tablet	0.38 USD	tablet
Benztropine mes 0.5 mg tablet	0.34 USD	tablet
Benztropine Mesylate 0.5 mg tablet	0.27 USD	tablet
Benztropine Mesylate 1 mg tablet	0.27 USD	tablet
Benztropine Mesylate 2 mg tablet	0.26 USD	tablet
Apo-Benztropine 2 mg Tablet	0.06 USD	tablet
Pms-Benztropine 2 mg Tablet	0.05 USD	tablet
Pms-Benztropine 1 mg Tablet	0.02 USD	tablet

Patents

Not Available

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
water solubility	Very soluble	PhysProp
logP	4.3	PhysProp

Predicted Properties

Property	Value	Source
water solubility	1.21e-03 g/l	ALOGPS
logP	4.47	ALOGPS
logP	4.19	ChemAxon Molconvert
logS	-5.41	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	2	ChemAxon Molconvert
hydrogen donor count	0	ChemAxon Molconvert
polar surface area	12.47	ChemAxon Molconvert
rotatable bond count	4	ChemAxon Molconvert
refractivity	94.24	ChemAxon Molconvert
polarizability	50.25	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Wszola BA, Newell KM, Sprague RL: Risk factors for tardive dyskinesia in a large population of youths and adults. Exp Clin Psychopharmacol. 2001 Aug;9(3):285-96. Pubmed
van Harten PN, Hoek HW, Matroos GE, Koeter M, Kahn RS: Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao Extrapyramidal Syndromes Study III. Am J Psychiatry. 1998 Apr;155(4):565-7. Pubmed

External Links

Resource	Link
KEGG Compound	C06846
PubChem Compound	6832
PubChem Substance	46505349
ChemSpider	6571
ChEBI	3048
ChEMBL	3048
Therapeutic Targets Database	DAP001460
PharmGKB	PA448591
Drug Product Database	706531
RxList	http://www.rxlist.com/cgi/generic2/benztrop.htm
Drugs.com	http://www.drugs.com/cdi/benztropine.html
Wikipedia	http://en.wikipedia.org/wiki/Benztropine

ATC Codes

N04AC01

AHFS Codes

28:36.08

PDB Entries

Not Available

FDA label

Not Available

MSDS

show (73.3 KB)

Interactions

Drug Interactions

Not Available

Food Interactions

Avoid alcohol.
Take with food to reduce irritation.

Targets
1. Muscarinic acetylcholine receptor M1 Pharmacological action: yes Actions: antagonist The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover Organism class: human UniProt ID: P11229 Gene: CHRM1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed 2. Sodium-dependent dopamine transporter Pharmacological action: yes Actions: inhibitor Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals Organism class: human UniProt ID: Q01959 Gene: SLC6A3 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Katz JL, Agoston GE, Alling KL, Kline RH, Forster MJ, Woolverton WL, Kopajtic TA, Newman AH: Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents. Psychopharmacology (Berl). 2001 Apr;154(4):362-74. Pubmed Kulkarni SS, Kopajtic TA, Katz JL, Newman AH: Comparative structure-activity relationships of benztropine analogues at the dopamine transporter and histamine H(1) receptors. Bioorg Med Chem. 2006 Jun 1;14(11):3625-34. Epub 2006 Feb 3. Pubmed Reith ME, Berfield JL, Wang LC, Ferrer JV, Javitch JA: The uptake inhibitors cocaine and benztropine differentially alter the conformation of the human dopamine transporter. J Biol Chem. 2001 Aug 3;276(31):29012-8. Epub 2001 Jun 6. Pubmed Simoni D, Roberti M, Rondanin R, Baruchello R, Rossi M, Invidiata FP, Merighi S, Varani K, Gessi S, Borea PA, Marino S, Cavallini S, Bianchi C, Siniscalchi A: Effects of two-carbon bridge region methoxylation of benztropine: discovery of novel chiral ligands for the dopamine transporter. Bioorg Med Chem Lett. 2001 Mar 26;11(6):823-7. Pubmed Todd CL, Grace AA: Interaction of benztropine and haloperidol actions on rat substantia nigra dopamine cell electrophysiological activity in vivo. Brain Res Bull. 1999 Jan 15;48(2):219-22. Pubmed Zou MF, Kopajtic T, Katz JL, Wirtz S, Justice JB Jr, Newman AH: Novel tropane-based irreversible ligands for the dopamine transporter. J Med Chem. 2001 Dec 6;44(25):4453-61. Pubmed 3. Histamine H1 receptor Pharmacological action: unknown Actions: antagonist In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system Organism class: human UniProt ID: P35367 Gene: HRH1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Kulkarni SS, Kopajtic TA, Katz JL, Newman AH: Comparative structure-activity relationships of benztropine analogues at the dopamine transporter and histamine H(1) receptors. Bioorg Med Chem. 2006 Jun 1;14(11):3625-34. Epub 2006 Feb 3. Pubmed

Targets

1. Muscarinic acetylcholine receptor M1

Pharmacological action: yes
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Organism class: human
UniProt ID: P11229 Link_out

Gene: CHRM1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Sodium-dependent dopamine transporter

Pharmacological action: yes
Actions: inhibitor

Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals

Organism class: human
UniProt ID: Q01959 Link_out

Gene: SLC6A3 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Katz JL, Agoston GE, Alling KL, Kline RH, Forster MJ, Woolverton WL, Kopajtic TA, Newman AH: Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents. Psychopharmacology (Berl). 2001 Apr;154(4):362-74. Pubmed
Kulkarni SS, Kopajtic TA, Katz JL, Newman AH: Comparative structure-activity relationships of benztropine analogues at the dopamine transporter and histamine H(1) receptors. Bioorg Med Chem. 2006 Jun 1;14(11):3625-34. Epub 2006 Feb 3. Pubmed
Reith ME, Berfield JL, Wang LC, Ferrer JV, Javitch JA: The uptake inhibitors cocaine and benztropine differentially alter the conformation of the human dopamine transporter. J Biol Chem. 2001 Aug 3;276(31):29012-8. Epub 2001 Jun 6. Pubmed
Simoni D, Roberti M, Rondanin R, Baruchello R, Rossi M, Invidiata FP, Merighi S, Varani K, Gessi S, Borea PA, Marino S, Cavallini S, Bianchi C, Siniscalchi A: Effects of two-carbon bridge region methoxylation of benztropine: discovery of novel chiral ligands for the dopamine transporter. Bioorg Med Chem Lett. 2001 Mar 26;11(6):823-7. Pubmed
Todd CL, Grace AA: Interaction of benztropine and haloperidol actions on rat substantia nigra dopamine cell electrophysiological activity in vivo. Brain Res Bull. 1999 Jan 15;48(2):219-22. Pubmed
Zou MF, Kopajtic T, Katz JL, Wirtz S, Justice JB Jr, Newman AH: Novel tropane-based irreversible ligands for the dopamine transporter. J Med Chem. 2001 Dec 6;44(25):4453-61. Pubmed

3. Histamine H1 receptor

Pharmacological action: unknown
Actions: antagonist

In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system

Organism class: human
UniProt ID: P35367 Link_out

Gene: HRH1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Kulkarni SS, Kopajtic TA, Katz JL, Newman AH: Comparative structure-activity relationships of benztropine analogues at the dopamine transporter and histamine H(1) receptors. Bioorg Med Chem. 2006 Jun 1;14(11):3625-34. Epub 2006 Feb 3. Pubmed

Enzymes
1. Cytochrome P450 2C19 Actions: substrate Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine UniProt ID: P33261 Gene: CYP2C19 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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 Gene: CYP2D6 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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

Enzymes

1. Cytochrome P450 2C19

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out

Gene: CYP2C19 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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 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:

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

Comments

Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:02

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.