Physostigmine
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| Trade names | Antilirium |
| AHFS/Drugs.com | Monograph |
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intravenous, intramuscular, ophthalmic |
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| Pharmacokinetic data | |
| Metabolism | Major metabolite: Eseroline |
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| ECHA InfoCard | 100.000.302 |
| Chemical and physical data | |
| Formula | C15H21N3O2 |
| Molar mass | 275.346 g/mol |
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Physostigmine (also known as eserine from éséré, the 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 Percy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade names Antilirium and Isopto Eserine, and as eserine salicylate and eserine sulfate. Today, physostigmine is most commonly used for its medicinal value but before its discovery by Sir Robert Christison in 1846, it was much more prevalent as a poison. The positive medical applications of the drug were first suggested in the gold medal winning final thesis of Thomas Richard Fraser at Edinburgh University in 1862.
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 an LD50 of 3 mg/kg in mice.
Combination of acetylcholine and physostigmine is an example of supra-additive phenomenon .
Physostigmine has two chiral carbon atoms. Therefore, attention needs to be paid to the synthesis of the correct diastereomers. The 71 syntheses of physostigmine yield 33 racemic mixtures and 38 products of a single enantiomer. The first total synthesis of physostigmine was achieved by Julian and Piki in 1935. The main goal of Julian’s physostigmine synthesis was to get the intermediate key compound, l-eseroline (compound 10 in the adjacent diagram). Then, this compound 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 compound 6 to given compound 7 in the diagram) 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. Although he succeeded in the synthesis of the target chemical, the route had several drawbacks. First, the chemical resolution of compound 8 is unreliable, and the chemical resolution of d,l-eserethole gives optically pure enantiomers after eight recrystallizations of its tartrate salt. Second, the reaction of compound 8 to give compound 9 requires a large amount of Na. In the years since this initial work, many other groups have used a variety of approaches to overcome these problems.
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