| Identification | More | [Name]
PHYSOSTIGMINE | [CAS]
57-47-6 | [Synonyms]
ESERINE
PHYSOSTIGMINE
(3as-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo(2,3-b)indol-5-olmeth
(3aS-cis)-1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-olmethylcarbamate (ester)
1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo-[2,3-b]indol-5-yl methylcarbamate
1,2,3,3abeta,8abeta-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]-indol-5-yl methylcarbamate
1,3a,8-Trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methylcarbamate
3-b)indol-5-ol,1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-pyrrolo(methylcarb
Antilirium
calabarine
Carbamic acid, methyl-, ester with eseroline
Cogmine Eserine
CS 58525
cs58525
Erserine
Eserolein, methylcarbamate
Eserolein, methylcarbamate (ester)
eserolein,methylcarbamate(ester)
Esromiotin
Ezerin | [EINECS(EC#)]
200-332-8 | [Molecular Formula]
C15H21N3O2 | [MDL Number]
MFCD00151090 | [Molecular Weight]
275.35 | [MOL File]
57-47-6.mol |
| Chemical Properties | Back Directory | [Appearance]
solid | [Melting point ]
102-104 °C(lit.) | [alpha ]
D17 -76° (c = 1.3 in chloroform); D25 -120° (benzene) | [Boiling point ]
418.29°C (rough estimate) | [density ]
1.166±0.06 g/cm3 (20 ºC 760 Torr) | [refractive index ]
1.5600 (estimate) | [Fp ]
>100℃ | [storage temp. ]
2-8°C
| [form ]
Powder | [pka]
6.12, 12.24(at 25℃) | [color ]
Off-white | [Water Solubility ]
Soluble in water (1:75), alcohol (1:10), chloroform (1:1), ether (1:30), and DMSO. | [Sensitive ]
Air & Light Sensitive | [Usage]
Physostigmine base (Eserine-Base) is used as bulk pharmaceuticals (parasympathomimetic, cholinergic, ophthalmic, anti-Alzheimer). Product Data Sheet | [Merck ]
7384 | [CAS DataBase Reference]
57-47-6(CAS DataBase Reference) | [EPA Substance Registry System]
Physostigmine (57-47-6) |
| Safety Data | Back Directory | [Hazard Codes ]
T+ | [Risk Statements ]
R26/28:Very Toxic by inhalation and if swallowed . | [Safety Statements ]
S23:Do not breathe gas/fumes/vapor/spray (appropriate wording to be specified by the manufacturer) .
S45:In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) .
S25:Avoid contact with eyes . | [RIDADR ]
UN 1544 6.1/PG 1
| [WGK Germany ]
3
| [RTECS ]
TJ2100000
| [F ]
8-10 | [TSCA ]
Yes | [HazardClass ]
6.1(a) | [PackingGroup ]
II | [Safety Profile]
A human poison by an
unspecified route. Poison experimentally by
ingestion, subcutaneous, intramuscular,
intravenous, and intraperitoneal routes.
Human systemic effects by ingestion:
nausea, dyspnea, coma, blood pressure
elevation, flaccid paralysis without
anesthesia, muscle weakness. Normally
administered by injection. Poisoning can
occur as a result of a mistake in dosage or
due to hypersensitivity of the patient withm
5 to 25 minutes after administration. Death
usually results from respiratory paralysis.
Experimental reproductive effects.
Combustible when exposed to heat or
flame. When heated to decomposition it
emits toxic fumes of NOx. See also
CARBAMATES. | [Hazardous Substances Data]
57-47-6(Hazardous Substances Data) | [Toxicity]
LD50 orally in mice: 4.5 mg/kg (Lynch, Coon) |
| Raw materials And Preparation Products | Back Directory | [Raw materials]
Hydrogen peroxide-->ZINC-->1H-Indole-3-acetaldehyde, 2,3-dihydro-5-methoxy-1,3-dimethyl-2-oxo-, (3S)--->2-Butenoic acid, 2-methyl-4-[[tris(1-methylethyl)silyl]oxy]-, (2Z)--->Benzenamine, 2-iodo-4-methoxy-N-methyl--->Eseroline-->(3aS,8aR)-5-methoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-->METHYLISOCYANATE 1 X 500MG NEAT |
| Hazard Information | Back Directory | [General Description]
White, odorless, microcrystalline powder. Used as a cholinergic (anticholinesterase) agent and as a veterinary medication. | [Health Hazard]
Super toxic. Probable oral lethal dose is less than 5 mg/kg for a 70 kg (150 lb.) person. Material is a cholinesterase inhibitor. Effects of exposure may involve the respiratory, gastrointestinal, cardiovascular and central nervous systems. Death occurs due to respiratory paralysis or impaired cardiac function. Time to death may vary from 5 minutes to 24 hours, in severely poisoned patients, depending on factors such as the dose and route. Persons with asthma and/or persons that require drugs containing choline esters are at risk. | [Potential Exposure]
Physostigmine, an alkaloid, originally derived from the calabar bean (Physostigma venenosum) isa potent and reversible inhibitor of cholinesterase. Material is used as a cholinergic (anticholinesterase) agent and as a veterinary medication. Although listed as a carbamate pesticide, physostigmine is not registered for use as an agricultural chemical in the United States. | [Fire Hazard]
PHYSOSTIGMINE is a slight fire hazard. When heated to decomposition PHYSOSTIGMINE emits toxic fumes of nitrogen oxides. Keep from light and heat. | [First aid]
If this chemical gets into the eyes, remove any contact lenses at once and irrigate immediately for at least 15 minutes, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin, remove contaminated clothing and wash immediately with soap and water. Seek medical attention immediately. If this chemical has been inhaled, remove from exposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR if heart action has stopped. Transfer promptly to a medical facility. When this chemical has been swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit. | [Shipping]
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN1544 Alkaloids, solid, n.o.s. or Alkaloid salts, solid, n.o.s. poisonous, Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. | [Incompatibilities]
Light and heat. | [Description]
The classic AChEI, physostigmine, is an alkaloid obtained from seeds of the Calabar bean (Physostigma venenosum). Its
parasympathomimetic effects were recognized long before its structure was elucidated in 1923. In 1929, Stedman found that the mechanism of
the parasympathomimetic effects of physostigmine was inhibition of AChE; it inhibits AChE by acting as a substrate and carbamylating the
enzyme. Acetylcholinesterase is carbamylated at a slow rate, but physostigmine has exceptionally high affinity (Ki ~ 10-9 M) for the catalytic site
of the enzyme. By comparison, the Ks for acetylcholine is on the order of 10-4 M. Thus, physostigmine is classified as a reversible AChEI that
carbamylates the enzyme at a slow rate; the carbamylated AChE also is regenerated quite slowly. Because physostigmine is a tertiary amine with
a pKa of 8.2 (+BH) rather than a quaternary ammonium salt, it is more lipophilic than many other AChEIs and can diffuse across the blood-brain barrier. The tertiary amine also imparts pH dependence to its ability to inhibit AChE, because its affinity for AChE is greater when the amine is
protonated. | [Chemical Properties]
Physostigmine is a white crystalline solid. Odorless. | [Waste Disposal]
It is not appropriate to dispose of expired or waste drugs or waste product such as lab chemicals by flushing them down the toilet or discarding them to the trash. Larger quantities shall carefully take into consideration applicable EPA, and FDA regulations. If possible return the lab chemicals to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste lab chemicals shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator. In accordance with 40CFR165, follow recommendations for the disposal of pesticides and pesticide containers. Must be disposed properly by following package label directions or by contacting your local or federal environmental control agency, or by contacting your regional EPA office. | [Physical properties]
Appearance: flaky crystal. Solubility: slightly soluble in water; soluble in ethanol,
benzene, and fatty oil. Melting point: 102–104 °C. Specific optical rotation: ?120°
in benzene and ?76° in chloroform, respectively | [History]
Eserine was first discovered as a reversible AChE inhibitor, and it is also a tertiary
amine and easily crosses the blood-brain barrier. In 1846, Robert Christison
observed that the extract from Calabar bean caused cardiac arrest and death; he
personally ate a certain amount of the extract and felt extremely feeble but luckily
survived. In 1855, Christison reported that some kind of substances in the Calabar
bean possessed strong biological activity.
In 1864, chemists afforded crystal pure extract which was named as eserine. After
that, Thomas Richard Fraser and Douglas Argyll Robertson cooperated to employ
eserine in experimental ophthalmology, and the results showed that the antagonistic
effect of eserine on mydriasis is induced by atropine. In 1875, Ludwig Laqueur
declared that eserine could also be employed to depress intraocular pressure and first
used as a treatment for glaucoma. In 1925, Edgar Stedman and George Barger determined
the structure of eserine, which belongs to a natural product whose structure is characterized with hexahydropyrroloindole. In 1935, Percy Lavon Julian completed
the chemical synthesis of its racemate for the first time . | [Uses]
It is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor obtained from the Calabar bean, used to treat glaucoma and delayed gastric emptying. | [Uses]
Physostigmine base (Eserine-Base) is used as bulk pharmaceuticals (parasympathomimetic, cholinergic, ophthalmic, anti-Alzheimer). Product Data Sheet | [Definition]
ChEBI: Physostigmine is a carbamate ester and an indole alkaloid. It has a role as a miotic, an EC 3.1.1.8 (cholinesterase) inhibitor and an antidote to curare poisoning. | [Brand name]
Eserine Sulfate (Ciba Vision, US Ophthalmics). | [Mechanism of action]
Physostigmine is easily absorbed from the gastrointestinal tract and other mucous membranes. Upon entering the bloodstream, it easily permeates the blood–brain barrier. It is
inactivated by cholinesterase of the plasma. Physostigmine has a minimal direct effect on
cholinesterase receptors. | [Pharmacology]
Eserine was first discovered as one of AChE inhibitors. AChE inhibitor is the same
as ACh, which can combine with cholinesterase, while AChE inhibitor will combine
more tightly with cholinesterase, which leads to slow hydrolysis, inactive enzyme,
cumulative ACh, and emergent biological activities . Although eserine does not
directly activate M and N receptor, it can cross the central nervous system and
strongly militate the central and peripheral nervous systems .
When locally using eserine in the eyes, the effect is similar to pilocarpine but
more powerful and durable. It can activate AChR of iridis sphincter, representing
that the pupil is narrowed and the intraocular pressure is depressed, which is more
obvious when being used to treat glaucoma patients. When being absorbed, the
effect of eserine is similar to neostigmine, which is called as M- and N-like effects,
representing that smooth muscle is activated strongly. After crossing the central
nervous system, eserine can inhibit the activities induced by AChE, and it is presented
as “activate previously, inhibit later.” It is noted that the effect of eserine is
dependent on the status of the central nervous system . | [Clinical Use]
Physostigmine was used first as a topical application inthe treatment of glaucoma. Its lipid solubility properties permitadequate absorption from ointment bases. It is used systemicallyas an antidote for atropine poisoning and otheranticholinergic drugs by increasing the duration of actionof ACh at cholinergic sites through inhibition of AChE.Physostigmine, along with other cholinomimetic drugs actingin the CNS, has been studied for use in the treatment ofAlzheimer disease. Cholinomimetics that are currentlyused or which have been recently evaluated in the treatmentof Alzheimer disease include donepezil, galantamine, metrifonate,rivastigmine, and tacrine. It is anticipated that thislist will continue to grow as the etiology of this disease becomesbetter understood. | [Synthesis]
Physostigmine, 1,3a,8-trimethyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]-
indol-5-yl-N-methylcarbamate (13.2.7), is an alkaloid isolated from the so-called grand
beans?aseeds of the poisonous African plant of the familia Physostigma venenosum.
Physostigmine is made synthetically in various ways [40¨C42], one of which being from pethoxymethylaniline, which is reacted with |á-bromopropionyl bromide in the presence of
aluminum chloride, giving 1,3-dimethyl-5-ethoxyindolin-2-one (13.2.1). Reacting this
with chloracetonitrile in the presence of sodium ethoxide gives 1,3-dimethyl-5-ethoxy-
3-cyanomethylindolin-2-one (13.2.2). The nitrile group is reduced to an amine group,
which is further methoxided, giving 1,3-dimethyl-5-ethoxy-3-(|? methylaminoethyl)
indolin-2-one (13.2.3). The carbonyl group of this compound is reduced, forming an
aminoalcohol (13.2.4), the dehydration of which leads to formation of 1,3a,8-trimethyl-
2,3,3a,8a-tetrahydropyrrolo[2,3b]-5-ethoxyindol (13.2.5). The ethoxy-protecting group is
removed by hydrogen bromide, giving a compound with a phenol hydroxyl group (13.2.6),
which is reacted with methylisocyanate, giving the desired physostigmine (13.2.7).
| [Veterinary Drugs and Treatments]
Physostigmine has been used for the adjunctive treatment of ivermectin
toxicity in dogs, as a provocative agent for the diagnosis of
narcolepsy in dogs and horses, and as a treatment for anticholinergic
toxicity. Because of the potential for serious adverse effects,
use of physostigmine as an antidote is generally reserved for very
serious toxicity affecting the CNS. Otherwise, safer alternatives
such as neostigmine or pyridostigmine are preferred.
While physostigmine has been used to antagonize the CNS depressant
effects of benzodiazepines in humans, it should not be
used for this purpose because of the potential toxicity and nonspecific
action of physostigmine. | [Metabolism]
Physostigmine is the tertiary amine that
are rapidly absorbed from the gastrointestinal tract, as
are tacrine, donepezil, and galanthamine, whereas quaternary
ammonium compounds are poorly absorbed
after oral administration. Nevertheless, quaternary ammonium
compounds like neostigmine and pyridostigmine
are orally active if larger doses are employed.
Only the quaternary ammonium inhibitors do not readily
enter the CNS. Because of their high lipid solubility
and low molecular weight, most of the organophosphates
are absorbed by all routes of administration;
even percutaneous exposure can result in the absorption
of sufficient drug to permit the accumulation of
toxic levels of these compounds. | [Purification Methods]
Eserine crystallises from Et2O or *C6H6 and forms an unstable low melting form m 86-87o [Harley-Mason & Jackson J Chem Soc 3651 1954, Wijnberg & Speckamp Tetrahedron 34 2399 1978]. [Beilstein 23/11 V 401.] |
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