|Systematic (IUPAC) name|
|Pregnancy cat.||C (US)|
|Legal status||℞-only (US)|
|Routes||intravenous, intramuscular, ophthalmic|
|Metabolism||Major metabolite: Eseroline|
|ATC code||S01 V03|
|Mol. mass||275.346 g/mol|
|(what is this?)|
Physostigmine (also known as eserine from éséré, West African name for the Calabar bean) 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.
Physostigmine acts by interfering with the metabolism of acetylcholine. 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 acetylcholine receptors.
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 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.
More recently, Mukund Kulkarni and his group from the University of Pune 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.
Physostigmine biosynthesis is proposed from tryptamine methylation and post-heterocyclization catalyzed by an unknown enzyme:
Physostigmine is used to treat glaucoma, Alzheimer's disease and delayed gastric emptying. It has been shown to improve 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 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. 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. Furthermore, lower doses of GHB produce a stronger action at the GHB receptor than the GABAB-receptor, resulting in a stimulating effect which would act synergistically with physostigmine and producing hyperstimulation when the GHB blood levels begin to drop.
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 acids derived for use as sedatives or hypnotics).
An overdose can cause cholinergic syndrome.
- Katzung, B. G.; Masters, S.; Trever, A. (2009). Basic and Clinical Pharmacology. McGraw Hill. p. 110. ISBN 978-0-07-160405-5.
- Julian, P. L.; Pikl, J. (1935). "Studies in the Indole Series. III. On the Synthesis of Physostigmine". Journal of the American Chemical Society 57 (3): 539–544. doi:10.1021/ja01306a046.
- Julian, P. L.; Pikl, J.; Boggess, D. (1934). "Studies in the Indole Series. II. Alkylation of 1-Methyl-3-Formyloxindole and a Synthesis of the Basic Ring Structure of Physostigmine". Journal of the American Chemical Society 56 (8): 1797–1801. doi:10.1021/ja01323a046.
- Potter, S. O. L. (1893). A Handbook of Materia Medica, Pharmacy and Therapeutics. London: P. Blakiston's. p. 53.
- Traub, S. J.; Nelson, L. S.; Hoffman, R. S. (2002). "Physostigmine as a treatment for gamma-hydroxybutyrate toxicity: a review". Journal of Toxicology. Clinical Toxicology 40 (6): 781–787. doi:10.1081/CLT-120015839. PMID 12475191.
- Zvosec, D. L.; Smith, S. W.; Litonjua, R.; Westfal, R. E. (2007). "Physostigmine for gamma-hydroxybutyrate coma: inefficacy, adverse events, and review". Clinical Toxicology 45 (3): 261–265. doi:10.1080/15563650601072159. PMID 17453877.
- Alzheimer Research Forum