Physostigmine
Encyclopedia
Physostigmine is a parasympathomimetic alkaloid
, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean
.
The chemical was synthesized for the first time in 1935 by the chemists Percy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade names Antilirium, Eserine Salicylate, Isopto Eserine, and Eserine Sulfate.
. It is a covalent (reversible - bond hydrolyzed and released) inhibitor of acetylcholinesterase
, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction. It indirectly stimulates
both nicotinic
and muscarinic
receptors.
The Julian physostigmine synthesis was started from phenacetin 1 because 1 was inexpensive. First, 1 was added to sodium powder and dimethyl sulfate under xylene while being heated to produce 2. Then, 2 was converted to anilide 3 by reacting with a-bromopropionyl bromide. When 3 was treated with an excess of aluminium chloride, the ethoxyl group of 3 was cleaved, and then heating and working up of the mass was done to give a high yield of 4. Next, 4 was ethylated by ethyl sulfate to produce 5. 5 was then treated with chloroacetoniltrile and sodium ethoxide or sodium to yield 6. The nitrile of 6 was reduced to the amine to give 7 by Palladium and hydrogen. The amine of 7 was methylated, then reacting with methyl iodide followed by hydrolysis to produce 8. By successive action of d-camphorsulfonic acid and d-tartaric acid, this amine was resolved into its enantiomers in excellent yield. As a result, l-amine of 8 was reduced by sodium and alcohol and yielded more than 80% of l-eserethole 9.
Because the yields of all the above steps were very good and those reactions required little time, l-eserethole was easy to achieve. 9 was then converted to l-eseroline 10 smoothly by dissolving it in petroleum ether and anhydrous aluminum chloride while gently boiling the mixture. The conversion of l-eseroline into physostigmine was easy to achieve by treating with methyl isocynate, which was described by Polonovski and Nitzberg. As a result, Julian had completely synthesized d,l-eserethole for the first time. Consequently, the first synthesis of physostigmine was completed.
However, there are drawbacks in Julian’s synthesis. First, the chemical resolution of 8 is unreliable, and the chemical resolution of d,l-eserethole 9 gives optically pure enantiomers after eight recrystallizations of its tartrate salt. Second, the reaction from 8 to 9 requires a large amount of Na. As a result, Julian’s synthesis needed to be improved.
Most recently, Mukund and his group have described a powerful method to construct the quaternary carbon center by using the Wittig olefination-Claisen rearrangement. The synthesis starts with the Wittig olefination of o-nitroacetophenone 11. 11 is reacted with allyloxymethylenetriphenylphosphorane to produce an allyl vinyl ether 12. 12 is an inseparable mixture of E- and Z- isomers, but the NMR signals of the E- and Z-isomers are well separated in the olefinic region. Therefore, the ratio (5:1) of these isomers is identified. The allyl vinyl ether 12 is then refluxed in xylene. This reaction goes through the Claisen rearrangement to yield 85% of 13. The aldehyde group of 13 is protected by adding p-TSA, ethylene glycol, and toluene while refluxing. Then, ozone gas and dimethyl sulfide are added into the solution in DCM at 00C and give the new aldehyde 14. This aldehyde is reduced to alcohol 15 by reacting with sodium borohydride in aqueous THF. The alcohol of 15 is converted to amine 16 by adding DIAD and triphenyl phosphine, followed by phthalimide. The reaction is later reacted with methylamine while refluxing. The nitro of 16 is then reacted with methanol, Raney nickel, and hydrogen to give diamine 17 in 82% yield. Acetal of 17 is hydrolyzed with p-TSA in refluxing aqueous THF to produce tricyclic compound 18 in 65% yields. 19 is easy to achieve by adding ethyl acetate, aqueous formalin and followed 10% catalytic, Pd-C, under hydrogen. Then, 19 is converted to esermethole 20, an intermediate in the synthesis of physostigmine. Esermethole 20 is achieved in 70% yield by adding N-bromosuccinimide (NBS) to DMF at 00C, and then sodium methoxide is added in the presence of cuprous iodide with heat. Finally, esermethole 20 is demethylated with boron tribromide; then the mixture is treated with phenol, NaH, THF, and methylisocyanate resulting in the crystalline product, Physostigmine. As a result, a new and efficient synthesis of physostigmine was successfully developed.
, glaucoma
, Alzheimer's disease
and delayed gastric emptying. It has been shown to improve the short term memory (Krus et al. 1968). Recently, it has begun to be used in the treatment of orthostatic hypotension
.
Because it is a tertiary amine (and thus does not hydrogen bond, making it more hydrophobic), it can cross the blood-brain barrier
, and physostigmine salicylate is used to treat the central nervous system
effects of atropine
, scopolamine
and other anticholinergic
drug overdoses.
Physostigmine is the antidote
of choice for Datura stramonium
poisoning. It is also an antidote for Atropa belladonna poisoning, the same as for atropine. It has been also used as an antidote for poisoning with GHB as well, but is poorly effective and often causes additional toxicity, so is not a recommended treatment.
Physostigmine also has a miotic function, causing pupillary constriction. It is useful in treating mydriasis
. Physostigmine also increases outflow of the aqueous humor in the eye, making it useful in the treatment of glaucoma.
Recently, physostigmine has been proposed as antidote for intoxication with gamma hydroxybutyrate (GHB, a potent sedative-hypnotic agent that can cause loss of consciousness, loss of muscle control, and death). Physostigmine may treat GHB by producing a nonspecific state of arousal. However, there is not enough scientific evidence to prove physostigmine properly treats GHB toxicity.
Physostigmine also has other proposed uses: it could reverse undesired side effects of benzodiazepines such as diazepam
, alleviating anxiety and tension. Another proposed use of physostigmine is to reverse the effects of barbiturates (any of a group of barbituric acid
s derived for use as sedatives or hypnotics).
.
Other side effects may include nausea
, vomiting
, diarrhea
, anorexia
, dizziness, headache, stomach pain, sweating, dyspepsia
and seizures.
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean
Calabar bean
The Calabar bean is the seed of a leguminous plant, Physostigma venenosum, a native of tropical Africa, poisonous to humans. It derives the first part of its scientific name from a curious beak-like appendage at the end of the stigma, in the centre of the flower; this appendage, though solid, was...
.
The chemical was synthesized for the first time in 1935 by the chemists Percy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade names Antilirium, Eserine Salicylate, Isopto Eserine, and Eserine Sulfate.
Pharmacology
Physostigmine acts by interfering with the metabolism of acetylcholineAcetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
. It is a covalent (reversible - bond hydrolyzed and released) inhibitor of acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction. It indirectly stimulates
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
both nicotinic
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
and muscarinic
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
receptors.
Syntheses
Physostigmine has two chiral carbon atoms. Therefore, attention needs to be paid to the synthesis of the correct diastereomers. There are 71 syntheses of physostigmine; 33 yield racemic mixtures, 38 yield a pure chiral product. The first total synthesis of physostigmine was achieved by Julian and Piki in 1935. It is summarized in Figure 3. The main goal of Julian’s physostigmine synthesis was to get the intermediate key compound, l-eseroline 10. Then, 10 would be easily converted to physostigmine. In one of his earlier works, “Studies in the Indole Series II,” Julian synthesized the ring of physostigmine from starting material, 1-methyl-3-formyl oxindole, which was discovered by Friedlander. However, he faced the problems that the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of 6 to 7) with sodium and alcohol did not result in good yield. In his second work “Studies in the Indole Series III,” he had improved the yield of amine from nitrile significantly by using palladium and hydrogen.The Julian physostigmine synthesis was started from phenacetin 1 because 1 was inexpensive. First, 1 was added to sodium powder and dimethyl sulfate under xylene while being heated to produce 2. Then, 2 was converted to anilide 3 by reacting with a-bromopropionyl bromide. When 3 was treated with an excess of aluminium chloride, the ethoxyl group of 3 was cleaved, and then heating and working up of the mass was done to give a high yield of 4. Next, 4 was ethylated by ethyl sulfate to produce 5. 5 was then treated with chloroacetoniltrile and sodium ethoxide or sodium to yield 6. The nitrile of 6 was reduced to the amine to give 7 by Palladium and hydrogen. The amine of 7 was methylated, then reacting with methyl iodide followed by hydrolysis to produce 8. By successive action of d-camphorsulfonic acid and d-tartaric acid, this amine was resolved into its enantiomers in excellent yield. As a result, l-amine of 8 was reduced by sodium and alcohol and yielded more than 80% of l-eserethole 9.
Because the yields of all the above steps were very good and those reactions required little time, l-eserethole was easy to achieve. 9 was then converted to l-eseroline 10 smoothly by dissolving it in petroleum ether and anhydrous aluminum chloride while gently boiling the mixture. The conversion of l-eseroline into physostigmine was easy to achieve by treating with methyl isocynate, which was described by Polonovski and Nitzberg. As a result, Julian had completely synthesized d,l-eserethole for the first time. Consequently, the first synthesis of physostigmine was completed.
However, there are drawbacks in Julian’s synthesis. First, the chemical resolution of 8 is unreliable, and the chemical resolution of d,l-eserethole 9 gives optically pure enantiomers after eight recrystallizations of its tartrate salt. Second, the reaction from 8 to 9 requires a large amount of Na. As a result, Julian’s synthesis needed to be improved.
Most recently, Mukund and his group have described a powerful method to construct the quaternary carbon center by using the Wittig olefination-Claisen rearrangement. The synthesis starts with the Wittig olefination of o-nitroacetophenone 11. 11 is reacted with allyloxymethylenetriphenylphosphorane to produce an allyl vinyl ether 12. 12 is an inseparable mixture of E- and Z- isomers, but the NMR signals of the E- and Z-isomers are well separated in the olefinic region. Therefore, the ratio (5:1) of these isomers is identified. The allyl vinyl ether 12 is then refluxed in xylene. This reaction goes through the Claisen rearrangement to yield 85% of 13. The aldehyde group of 13 is protected by adding p-TSA, ethylene glycol, and toluene while refluxing. Then, ozone gas and dimethyl sulfide are added into the solution in DCM at 00C and give the new aldehyde 14. This aldehyde is reduced to alcohol 15 by reacting with sodium borohydride in aqueous THF. The alcohol of 15 is converted to amine 16 by adding DIAD and triphenyl phosphine, followed by phthalimide. The reaction is later reacted with methylamine while refluxing. The nitro of 16 is then reacted with methanol, Raney nickel, and hydrogen to give diamine 17 in 82% yield. Acetal of 17 is hydrolyzed with p-TSA in refluxing aqueous THF to produce tricyclic compound 18 in 65% yields. 19 is easy to achieve by adding ethyl acetate, aqueous formalin and followed 10% catalytic, Pd-C, under hydrogen. Then, 19 is converted to esermethole 20, an intermediate in the synthesis of physostigmine. Esermethole 20 is achieved in 70% yield by adding N-bromosuccinimide (NBS) to DMF at 00C, and then sodium methoxide is added in the presence of cuprous iodide with heat. Finally, esermethole 20 is demethylated with boron tribromide; then the mixture is treated with phenol, NaH, THF, and methylisocyanate resulting in the crystalline product, Physostigmine. As a result, a new and efficient synthesis of physostigmine was successfully developed.
Clinical uses
Physostigmine is used to treat myasthenia gravisMyasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
, glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and delayed gastric emptying. It has been shown to improve the short term memory (Krus et al. 1968). Recently, it has begun to be used in the treatment of orthostatic hypotension
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
.
Because it is a tertiary amine (and thus does not hydrogen bond, making it more hydrophobic), it can cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, and physostigmine salicylate is used to treat the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
effects of atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
, scopolamine
Scopolamine
Scopolamine, also known as levo-duboisine, and hyoscine, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from Solanaceae family of plants, such as henbane, jimson weed and Angel's Trumpets , and corkwood...
and other anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
drug overdoses.
Physostigmine is the antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
of choice for Datura stramonium
Datura stramonium
Datura stramonium, known by the common names Jimson weed, devil's trumpet, devil's weed, thorn apple, tolguacha, Jamestown weed, stinkweed, locoweed, datura, pricklyburr, devil's cucumber, Hell's Bells, moonflower and, in South Africa, malpitte and mad seeds, is a common weed in the...
poisoning. It is also an antidote for Atropa belladonna poisoning, the same as for atropine. It has been also used as an antidote for poisoning with GHB as well, but is poorly effective and often causes additional toxicity, so is not a recommended treatment.
Bioactivity
Physostigmine functions as an acetylcholinesterase inhibitor. Its mechanism is to prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of acetylcholine. This inhibition enhances the effect of acetylcholine, making it useful for the treatment of cholinergic disorders and myasthenia gravis. More recently, physostigmine has been used to improve the memory of Alzheimer’s patients due to its potent anticholinesterase activity. However, the drug form of physostigmine, physostigmine salicylate, has poor bioavailability.Physostigmine also has a miotic function, causing pupillary constriction. It is useful in treating mydriasis
Mydriasis
Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
. Physostigmine also increases outflow of the aqueous humor in the eye, making it useful in the treatment of glaucoma.
Recently, physostigmine has been proposed as antidote for intoxication with gamma hydroxybutyrate (GHB, a potent sedative-hypnotic agent that can cause loss of consciousness, loss of muscle control, and death). Physostigmine may treat GHB by producing a nonspecific state of arousal. However, there is not enough scientific evidence to prove physostigmine properly treats GHB toxicity.
Physostigmine also has other proposed uses: it could reverse undesired side effects of benzodiazepines such as diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, alleviating anxiety and tension. Another proposed use of physostigmine is to reverse the effects of barbiturates (any of a group of barbituric acid
Barbituric acid
Barbituric acid or malonylurea or 6-hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in water. Barbituric acid is the parent compound of barbiturate drugs, although barbituric acid itself is not pharmacologically active...
s derived for use as sedatives or hypnotics).
Side effects
An overdose can cause cholinergic syndromeSLUD
SLUDGE is a mnemonic of a pathological effects indicative of massive discharge of the parasympathetic nervous system. Unlikely to occur naturally, SLUDGE is usually encountered only in cases of drug overdose, ingestion of certain poisonous mushrooms , or exposure to nerve...
.
Other side effects may include nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, dizziness, headache, stomach pain, sweating, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
and seizures.