Chemistry:Eseroline
Eseroline is a drug which acts as an opioid agonist.[1] It is a metabolite of the acetylcholinesterase inhibitor physostigmine but unlike physostigmine, the acetylcholinesterase inhibition produced by eseroline is weak and easily reversible,[2][3] and it produces fairly potent analgesic effects mediated through the μ-opioid receptor.[4] This mixture of activities gives eseroline an unusual pharmacological profile,[5][6] although its uses are limited by side effects such as respiratory depression[7] and neurotoxicity.[8]
Synthesis
The alkylation of phenacetin (1) with dimethyl sulfate gives N-methylphenetidine (2). Treatment with 2-bromopropanoyl bromide gives 2-bromo-N-(4-ethoxyphenyl)-N-methylpropanamide (3). Treatment with aluminium trichloride results in 1,3-dimethyl-5-hydroxyoxindole (4). Alkylation with diethyl sulfate gives 5-ethoxy-1,3-dimethylindolin-2-one (5). Base-catalyzed treatment with chloroacetonitrile gives 2-(5-ethoxy-1,3-dimethyl-2-oxoindol-3-yl)acetonitrile (6). Catalytic hydrogenation of the nitrile group gives (7). Mono-methylation of the primary amine gives (8). Intramolecular reductive amination gives eserethole (9). Cleavage of the ethyl ether protecting group gave (-)-eseroline (10). Optional treatment with methyl isocyanide (MIC) leads to physostigmine.
References
- ↑ "Direct evidence that eseroline possesses morphine-like effects". European Journal of Pharmacology 83 (3–4): 233–41. September 1982. doi:10.1016/0014-2999(82)90256-4. PMID 6293841.
- ↑ "Opiatelike actions of eseroline, an eserine derivative". Canadian Journal of Physiology and Pharmacology 59 (3): 307–10. March 1981. doi:10.1139/y81-048. PMID 7194726.
- ↑ "Reversible inhibition of acetylcholinesterase by eseroline, an opioid agonist structurally related to physostigmine (eserine) and morphine". Biochemical Pharmacology 31 (7): 1233–8. April 1982. doi:10.1016/0006-2952(82)90009-0. PMID 7092918.
- ↑ "Structure--activity relationships of eseroline and morphine: ab initio quantum-chemical study of the electrostatic potential and of the interaction energy with water". Molecular Pharmacology 18 (3): 461–7. November 1980. PMID 7464812.
- ↑ "Reversible inhibition of cholinesterases by opioids: possible pharmacological consequences". The Journal of Pharmacy and Pharmacology 48 (11): 1164–8. November 1996. doi:10.1111/j.2042-7158.1996.tb03914.x. PMID 8961166.
- ↑ "Effect of eseroline on schedule-controlled behavior in the rat". Pharmacology, Biochemistry, and Behavior 38 (4): 747–51. April 1991. doi:10.1016/0091-3057(91)90236-U. PMID 1871191.
- ↑ "Effects of eseroline on the ventilatory response to CO2". European Journal of Pharmacology 232 (1): 21–8. February 1993. doi:10.1016/0014-2999(93)90723-U. PMID 8458393.
- ↑ "Eseroline, a metabolite of physostigmine, induces neuronal cell death". Toxicology and Applied Pharmacology 106 (1): 28–37. October 1990. doi:10.1016/0041-008X(90)90102-Z. PMID 2251681. Bibcode: 1990ToxAP.106...28S. https://zenodo.org/record/1258264.
- ↑ "A novel and efficient total synthesis of (±)-physostigmine". Tetrahedron Letters 50 (20): 2411–2413. 2009. doi:10.1016/j.tetlet.2009.03.012.
- ↑ "Hydroxytryptamines. Part II. A new synthesis of physostigmine.". Journal of the Chemical Society (Resumed): 3651-3654. 1954. doi:10.1039/JR9540003651.
- ↑ "New total synthesis of dl-physostigmine (dl-eserine) via regioselective NaBH4-reduction of imides.". Tetrahedron 34 (15): 2399-2404. January 1978. doi:10.1016/0040-4020(78)89058-9.
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