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Identification
NameAmbenonium
Accession NumberDB01122  (APRD00771)
TypeSmall Molecule
GroupsApproved
Description

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

Structure
Thumb
Synonyms
SynonymLanguageCode
AmbenoniumNot AvailableNot Available
Ambenonium baseNot AvailableNot Available
AmbenonumNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
MysuranNot Available
MytelaseNot Available
Brand mixturesNot Available
Categories
CAS number7648-98-8
WeightAverage: 537.565
Monoisotopic: 536.268482022
Chemical FormulaC28H42Cl2N4O2
InChI KeyOMHBPUNFVFNHJK-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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentAlpha Amino Acid Amides
Alternative parentsChlorobenzenes; Aryl Chlorides; Secondary Carboxylic Acid Amides; Enolates; Carboxylic Acids; Polyamines; Organochlorides
Substituentschlorobenzene; aryl chloride; aryl halide; benzene; carboxamide group; secondary carboxylic acid amide; polyamine; enolate; carboxylic acid; amine; organohalogen; organochloride; organonitrogen compound
Classification descriptionThis compound belongs to the alpha amino acid amides. These are amide derivatives of alpha amino acids.
Pharmacology
IndicationAmbenonium is used to treat muscle weakness due to muscle disease (myasthenia gravis).
PharmacodynamicsAmbenonium, 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 actionAmbenonium 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.
AbsorptionOral - poorly absorbed from the gastrointestinal tract.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Plasma and hepatic

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityLD50=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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.9618
Blood Brain Barrier + 0.8373
Caco-2 permeable + 0.5168
P-glycoprotein substrate Substrate 0.8725
P-glycoprotein inhibitor I Non-inhibitor 0.6717
P-glycoprotein inhibitor II Non-inhibitor 0.766
Renal organic cation transporter Non-inhibitor 0.823
CYP450 2C9 substrate Non-substrate 0.7865
CYP450 2D6 substrate Non-substrate 0.7008
CYP450 3A4 substrate Substrate 0.5842
CYP450 1A2 substrate Non-inhibitor 0.9046
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Non-inhibitor 0.6899
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8308
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.538
Ames test Non AMES toxic 0.7312
Carcinogenicity Non-carcinogens 0.6118
Biodegradation Not ready biodegradable 0.9927
Rat acute toxicity 2.4379 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9665
hERG inhibition (predictor II) Inhibitor 0.8507
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
Packagers
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Mytelase 10 mg caplet1.86USDcaplet
Mytelase 10 mg tablet1.86USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point196-199 °CKirchner, F.K.; U.S. Patent 3,096,373; July 2,1963; assigned to Sterling Drug Inc.
water solubilitySolubleNot Available
Predicted Properties
PropertyValueSource
Water Solubility9.42e-07ALOGPS
logP2.27ALOGPS
logP-3.6ChemAxon
logS-8.8ALOGPS
pKa (Strongest Acidic)10.78ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area58.2 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity173.57 m3·mol-1ChemAxon
Polarizability59.98 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Kirchner, F.K.; U.S. Patent 3,096,373; July 2,1963; assigned to Sterling Drug Inc.

General ReferenceNot Available
External Links
ResourceLink
KEGG CompoundC07773
PubChem Compound2131
PubChem Substance46508143
ChemSpider2046
ChEBI2627
ChEMBLCHEMBL1652
Therapeutic Targets DatabaseDAP000893
PharmGKBPA164764601
Drugs.comhttp://www.drugs.com/cdi/ambenonium.html
WikipediaAmbenonium
ATC CodesN07AA30
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(166 KB)
Interactions
Drug Interactions
Drug
BetamethasoneThe corticosteroid, betamethasone, may decrease the effect of the anticholinesterase, ambenonium.
DexamethasoneThe corticosteroid, dexamethasone, may decrease the effect of the anticholinesterase, ambenonium.
FludrocortisoneThe corticosteroid, fludrocortisone, may decrease the effect of the anticholinesterase, ambenonium.
HydrocortisoneThe corticosteroid, hydrocortisone, may decrease the effect of the anticholinesterase, ambenonium.
PrednisoloneThe corticosteroid, prednisolone, may decrease the effect of the anticholinesterase, ambenonium.
PrednisoneThe corticosteroid, prednisone, may decrease the effect of the anticholinesterase, ambenonium.
TacrineThe acetylcholinesterase inhibitor, Tacrine, may increase the adverse/toxic effects of Ambenonium, a cholinergic agonist. Monitor for increased cholinergic effects and toxicity.
TriamcinoloneThe corticosteroid, triamcinolone, may decrease the effect of the anticholinesterase, ambenonium.
Food InteractionsNot Available

Targets

1. Acetylcholinesterase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Acetylcholinesterase P22303 Details

References:

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cholinesterase

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Cholinesterase P06276 Details

References:

  1. 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

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Drug created on June 13, 2005 07:24 / Updated on March 27, 2014 13:54