AMBENONIUM

US Previously Marketed

First approved in 1956

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H42Cl2N4O2
Molecular Weight	537.565
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	2

SHOW SMILES / InChI

Structure Search

SMILES

CC[N+](CC)(CCNC(=O)C(=O)NCC[N+](CC)(CC)CC1=C(Cl)C=CC=C1)CC2=C(Cl)C=CC=C2

InChI

InChIKey=OMHBPUNFVFNHJK-UHFFFAOYSA-P

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

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010155s022lbl.pdf | https://www.drugbank.ca/drugs/DB01122

Ambenonium is a cholinesterase inhibitor with all the pharmacologic actions of acetylcholine, both the muscarinic and nicotinic types. It was marketed under the brand name Mytelase, but was withdrawn from the market in the United States in 2010. Ambenonium, similar to pyridostigmine and neostigmine, is used for the treatment of muscle weakness and fatigue in people with myasthenia gravis.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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Acetylcholinesterase 207 Target ID: CHEMBL220 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010155s022lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/21397501 \| https://www.ncbi.nlm.nih.gov/pubmed/21236521 \| https://www.ncbi.nlm.nih.gov/pubmed/13679187	Inhibitor 8297		0.7 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Myasthenia gravis 21 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010155s022lbl.pdf	Primary		Approved 8429	MYTELASE Approved Use This drug is indicated for the treatment of myasthenia gravis. Launch Date 1956

C_max

Value	Dose	Analyte	Population
0.129 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1823874/	10 mg 4 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
0.812 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1823874/	5 mg 4 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
1.29 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
2.5 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
5.61 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
9.12 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
8.4 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2613842/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
1.38 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1823874/	10 mg 4 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
6.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1823874/	5 mg 4 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
0.112 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
0.23 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
0.5 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1.07 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1516600/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	AMBENONIUM serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
5 mg 4 times / day multiple, oral Dose: 5 mg, 4 times / day Route: oral Route: multiple Dose: 5 mg, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 31 years n = 1 Health Status: unhealthy Condition: chronic cystitis Age Group: 31 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	Disc. AE: Muscle weakness, Fatigue... AEs leading to discontinuation/dose reduction: Muscle weakness (1 patient) Fatigue (1 patient) Chest pain (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/14234274
10 mg 3 times / 2 days multiple, oral Dose: 10 mg, 3 times / 2 days Route: oral Route: multiple Dose: 10 mg, 3 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 81 years n = 1 Health Status: unhealthy Condition: pernicious anemia Age Group: 81 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	Disc. AE: Muscle weakness, Nausea... AEs leading to discontinuation/dose reduction: Muscle weakness (1 patient) Nausea (1 patient) Abdominal pain (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/14234274
1000 mg 1 times / day multiple, oral Studied dose Dose: 1000 mg, 1 times / day Route: oral Route: multiple Dose: 1000 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	Sources: https://pubmed.ncbi.nlm.nih.gov/14234274

AEs

AE	Significance	Dose	Population
Chest pain	1 patient Disc. AE	5 mg 4 times / day multiple, oral Dose: 5 mg, 4 times / day Route: oral Route: multiple Dose: 5 mg, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 31 years n = 1 Health Status: unhealthy Condition: chronic cystitis Age Group: 31 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274
Fatigue	1 patient Disc. AE	5 mg 4 times / day multiple, oral Dose: 5 mg, 4 times / day Route: oral Route: multiple Dose: 5 mg, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 31 years n = 1 Health Status: unhealthy Condition: chronic cystitis Age Group: 31 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274
Muscle weakness	1 patient Disc. AE	5 mg 4 times / day multiple, oral Dose: 5 mg, 4 times / day Route: oral Route: multiple Dose: 5 mg, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 31 years n = 1 Health Status: unhealthy Condition: chronic cystitis Age Group: 31 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274
Abdominal pain	1 patient Disc. AE	10 mg 3 times / 2 days multiple, oral Dose: 10 mg, 3 times / 2 days Route: oral Route: multiple Dose: 10 mg, 3 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 81 years n = 1 Health Status: unhealthy Condition: pernicious anemia Age Group: 81 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274
Muscle weakness	1 patient Disc. AE	10 mg 3 times / 2 days multiple, oral Dose: 10 mg, 3 times / 2 days Route: oral Route: multiple Dose: 10 mg, 3 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 81 years n = 1 Health Status: unhealthy Condition: pernicious anemia Age Group: 81 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274
Nausea	1 patient Disc. AE	10 mg 3 times / 2 days multiple, oral Dose: 10 mg, 3 times / 2 days Route: oral Route: multiple Dose: 10 mg, 3 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/14234274	unhealthy, 81 years n = 1 Health Status: unhealthy Condition: pernicious anemia Age Group: 81 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/14234274

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:2627	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:2627
MolPort	MolPort-006-167-711	https://www.molport.com/shop/molecule-link/MolPort-006-167-711
ZINC	ZINC000003995599	http://zinc15.docking.org/substances/ZINC000003995599

PubMed

Title	Date	PubMed
Effects of acetylcholinesterase inhibitors on the metabolism of amyloid precursor protein in vitro.	2001	11558939
Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors.	2001 Apr	11330337
Reversible and irreversible acetylcholinesterase inhibitors cause changes in neuronal amyloid precursor protein processing and protein kinase C level in vitro.	2001 Mar	11099780
Thyroid gland tumour, pemphigus foliaceus and myasthenia gravis in the daughter of a woman with myasthenia gravis.	2001 Sep	11678876
Sequence of a cDNA encoding acetylcholinesterase from susceptible and resistant two-spotted spider mite, Tetranychus urticae.	2003 May	12706630
Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors.	2003 Sep	13679187
[Biochemical characteristics of cholinesterase from taenia Hymenolepis diminuta].	2004	16862815
Identification and quantitation of six non-depolarizing neuromuscular blocking agents by LC-MS in biological fluids.	2004 Mar	15068563
[Nephrotic syndrome after extended thymectomy for thymoma with myasthenia gravis; report of a case].	2006 Mar	16529002
Similarities between CSF-brain extracellular transfer and neurofibrillary tangle invasion in Alzheimer's disease.	2006 Mar	15982786
Activation of group II metabotropic glutamate receptors reduces directional selectivity in retinal ganglion cells.	2006 Nov 29	17010323
Concurrence of non-myasthenic symptoms with myasthenia gravis.	2007 Apr	17464478
Characterization of reversible and pseudo-irreversible acetylcholinesterase inhibitors by means of an immobilized enzyme reactor.	2007 Mar 9	17134713
Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens.	2008 Aug	18033235
Preoperative steroid therapy stabilizes postoperative respiratory conditions in myasthenia gravis.	2008 Mar	18340510
Preoperative steroid therapy stabilizes postoperative respiratory condition in myasthenia gravis.	2008 Mar	18340506
AChR deficiency due to epsilon-subunit mutations: two common mutations in the Netherlands.	2009 Oct	19544078

Patents

Sample Use Guides

In Vivo Use Guide

For the patient with moderately severe myasthenia, from 5 mg to 25 mg of MYTELASE three or four times daily is an effective dose. In some patients a 5 mg dose is effective, whereas other patients require as much as from 50 mg to 75 mg per dose. The physician should start with a 5 mg dose, carefully observing the effect of the drug on the patient. The dosage may then be increased gradually to determine the effective and safe dose.

Route of Administration: Oral

In Vitro Use Guide

Inhibitory constant of ambenonium to bovine erythrocyte AChE determined in vitro was 3.7 nM.

Name

Type

Language

AMBENONIUM

Common Name

English

BENZENEMETHANAMINIUM, N,N'-((1,2-DIOXO-1,2-ETHANEDIYL)BIS(IMINO-2,1-ETHANEDIYL))BIS(2-CHLORO-N',N'-DIETHYL-

Common Name

English

OXALYLBIS(IMINOETHYLENE))BIS((O-CHLOROBENZYL)DIETHYLAMMONIUM

Common Name

English

AMBENONIUM ION

Common Name

English

Ambenonium [WHO-DD]

Common Name

English

AMBENONIUM CATION

Common Name

English

AMBENONIUM [VANDF]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000000177