DrugBank: Ambenonium (DB01122)

targets (1) enzymes (1)

Identification

Name

Ambenonium

Accession Number

DB01122 (APRD00771)

Type

small molecule

Groups

approved

Description

Ambenonium is a cholinesterase inhibitor used in the management of myasthenia gravis. [Wikipedia]

Structure

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

Synonyms

Ambenonum

Salts

Not Available

Brand names

Name	Company
Mytelase

Brand mixtures

Not Available

Categories

Antiarrhythmic Agents
Antimyasthenics

CAS number

7648-98-8

Weight

Average: 537.565
Monoisotopic: 536.268482022

Chemical Formula

C₂₈H₄₂Cl₂N₄O₂

InChI Key

InChIKey=OMHBPUNFVFNHJK-UHFFFAOYSA-P

InChI

InChI=1S/C28H40Cl2N4O2/c1-5-33(6-2,21-23-13-9-11-15-25(23)29)19-17-31-27(35)28(36)32-18-20-34(7-3,8-4)22-24-14-10-12-16-26(24)30/h9-16H,5-8,17-22H2,1-4H3/p+2

Plain Text

IUPAC Name

[(2-chlorophenyl)methyl](2-{[(2-{[(2-chlorophenyl)methyl]diethylazaniumyl}ethyl)carbamoyl]formamido}ethyl)diethylazanium

SMILES

CC[N+](CC)(CCNC(=O)C(=O)NCC[N+](CC)(CC)CC1=CC=CC=C1Cl)CC1=CC=CC=C1Cl

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Benzene and Derivatives
Halobenzenes

Substructures

Amino Ketones
Benzene and Derivatives
Aryl Halides
Carboxylic Acids and Derivatives
Halobenzenes
Quaternary Ammonium Salts
Aromatic compounds
Carboxamides and Derivatives
Cations

Pharmacology

Indication

Ambenonium is used to treat muscle weakness due to muscle disease (myasthenia gravis).

Pharmacodynamics

Ambenonium, similar to pyridostigmine and neostigmine, is used for the treatment of muscle weakness and fatigue in people with myasthenia gravis. It is postulated to exert its therapeutic effect by enhancing cholinergic function through the inhibition of the acetylcholine hydrolysis by acetylcholinesterase. Increased levels of acetylcholine has peripheral effects, as acetylcholine is also used in the brain, where it tends to cause excitatory actions. The glands that receive impulses from the parasympathetic part of the autonomic nervous system are also stimulated in the same way. This is why an increase in acetylcholine causes a decreased heart rate and increased production of saliva. Ambenonium is used less commonly than neostigmine or pyridostigmine but may be preferred in patients hypersensitive to the bromide ion. Ambenonium produces fewer muscarinic side effects than neostigmine, but more than pyridostigmine.

Mechanism of action

Ambenonium exerts its actions against myasthenia gravis by competitive, reversible inhibition of acetylcholinesterase. The disease myasthenia gravis occurs when the body inappropriately produces antibodies against acetylcholine receptors, and thus inhibits proper acetylcholine signal transmission (when acetylcholine binds to acetylcholine receptors of striated muscle fibers, it stimulates those fibers to contract). Ambenonium reversibly binds acetylcholinesterase at the anionic site, which results in the blockage of the site of acetycholine binding, thereby inhibiting acetylcholine hydrolysis and enhancing cholinergic function through the accumulation of acetycholine at cholinergic synpases. In turn this facilitates transmission of impulses across the myoneural junction and effectively treats the disease.

Absorption

Oral - poorly absorbed from the gastrointestinal tract.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Plasma and hepatic

Route of elimination

Not Available

Half life

Not Available

Clearance

Not Available

Toxicity

LD₅₀=150±44 mg/kg (orally in mice). Symptoms of overdose include muscle twitching, weakness and paralysis of voluntary muscles including the tongue, shoulders, neck and arms, blood pressure increase (with or without a slowing of heart rate), a sensation of internal trembling, severe anxiety, and panic. Death may occur rapidly if untreated.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Sanofi aventis us llc

Packagers

Dosage forms

Not Available

Prices

Unit description	Cost	Unit
Mytelase 10 mg caplet	1.86 USD	caplet
Mytelase 10 mg tablet	1.86 USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

solid

Experimental Properties

Property	Value	Source
melting point	196-199 °C	Not Available
water solubility	Soluble	Not Available

Predicted Properties

Property	Value	Source
water solubility	9.42e-07 g/l	ALOGPS
logP	2.27	ALOGPS
logP	-3.6	ChemAxon
logS	-8.8	ALOGPS
pKa (strongest acidic)	10.78	ChemAxon
pKa (strongest basic)	-3.6	ChemAxon
physiological charge	2	ChemAxon
hydrogen acceptor count	2	ChemAxon
hydrogen donor count	2	ChemAxon
polar surface area	58.2	ChemAxon
rotatable bond count	15	ChemAxon
refractivity	173.57	ChemAxon
polarizability	59.98	ChemAxon

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Compound	C07773
PubChem Compound	2131
PubChem Substance	46508143
ChemSpider	2046
ChEBI	2627
ChEMBL	2627
Therapeutic Targets Database	DAP000893
PharmGKB	PA164764601
Drugs.com	http://www.drugs.com/cdi/ambenonium.html
Wikipedia	http://en.wikipedia.org/wiki/Ambenonium

ATC Codes

N07AA30

AHFS Codes

Not Available

PDB Entries

Not Available

FDA label

Not Available

MSDS

show (166 KB)

Interactions

Drug Interactions

Drug	Interaction
Betamethasone	The corticosteroid, betamethasone, may decrease the effect of the anticholinesterase, ambenonium.
Dexamethasone	The corticosteroid, dexamethasone, may decrease the effect of the anticholinesterase, ambenonium.
Fludrocortisone	The corticosteroid, fludrocortisone, may decrease the effect of the anticholinesterase, ambenonium.
Hydrocortisone	The corticosteroid, hydrocortisone, may decrease the effect of the anticholinesterase, ambenonium.
Prednisolone	The corticosteroid, prednisolone, may decrease the effect of the anticholinesterase, ambenonium.
Prednisone	The corticosteroid, prednisone, may decrease the effect of the anticholinesterase, ambenonium.
Tacrine	The acetylcholinesterase inhibitor, Tacrine, may increase the adverse/toxic effects of Ambenonium, a cholinergic agonist. Monitor for increased cholinergic effects and toxicity.
Triamcinolone	The corticosteroid, triamcinolone, may decrease the effect of the anticholinesterase, ambenonium.

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 Gene: ACHE Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Lockhart B, Closier M, Howard K, Steward C, Lestage P: Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2001 Apr;363(4):429-38. Pubmed Hodge AS, Humphrey DR, Rosenberry TL: Ambenonium is a rapidly reversible noncovalent inhibitor of acetylcholinesterase, with one of the highest known affinities. Mol Pharmacol. 1992 May;41(5):937-42. Pubmed Papp MI, Komoly S, Szirmai IG, Kovacs T: Similarities between CSF-brain extracellular transfer and neurofibrillary tangle invasion in Alzheimer’s disease. Neurobiol Aging. 2006 Mar;27(3):402-12. Epub 2005 Jun 27. Pubmed Kenakin TP, Beek D: Self-cancellation of drug properties as a mode of organ selectivity: the antimuscarinic effects of ambenonium. J Pharmacol Exp Ther. 1985 Mar;232(3):732-40. Pubmed Webb GD: Affinity of benzoquinonium and ambenonium derivatives for the acetylcholine receptor, tested on the electroplax, and for acetylcholinesterase in solution. Biochim Biophys Acta. 1965 May 25;102(1):172-84. Pubmed Bolognesi ML, Cavalli A, Andrisano V, Bartolini M, Banzi R, Antonello A, Rosini M, Melchiorre C: Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors. Farmaco. 2003 Sep;58(9):917-28. Pubmed Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

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:

Lockhart B, Closier M, Howard K, Steward C, Lestage P: Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2001 Apr;363(4):429-38. Pubmed
Hodge AS, Humphrey DR, Rosenberry TL: Ambenonium is a rapidly reversible noncovalent inhibitor of acetylcholinesterase, with one of the highest known affinities. Mol Pharmacol. 1992 May;41(5):937-42. Pubmed
Papp MI, Komoly S, Szirmai IG, Kovacs T: Similarities between CSF-brain extracellular transfer and neurofibrillary tangle invasion in Alzheimer’s disease. Neurobiol Aging. 2006 Mar;27(3):402-12. Epub 2005 Jun 27. Pubmed
Kenakin TP, Beek D: Self-cancellation of drug properties as a mode of organ selectivity: the antimuscarinic effects of ambenonium. J Pharmacol Exp Ther. 1985 Mar;232(3):732-40. Pubmed
Webb GD: Affinity of benzoquinonium and ambenonium derivatives for the acetylcholine receptor, tested on the electroplax, and for acetylcholinesterase in solution. Biochim Biophys Acta. 1965 May 25;102(1):172-84. Pubmed
Bolognesi ML, Cavalli A, Andrisano V, Bartolini M, Banzi R, Antonello A, Rosini M, Melchiorre C: Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors. Farmaco. 2003 Sep;58(9):917-28. Pubmed
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes
1. Cholinesterase An acylcholine + H(2)O = choline + a carboxylate UniProt ID: P06276 Gene: BCHE Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Yamamoto K, Kohda Y, Sawada Y, Iga T: Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats. Biopharm Drug Dispos. 1991 Nov;12(8):613-25. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19