Eseroline

Eseroline
Clinical data
Other names	Eseroline
ATC code	none;
Identifiers
	IUPAC name (3aR,8bS)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-ol;
CAS Number	469-22-7 ;
PubChem CID	119198;
ChemSpider	106485;
UNII	Q22H41O18D;
ChEBI	CHEBI:48845;
CompTox Dashboard (EPA)	DTXSID30891448 ;
Chemical and physical data
Formula	C13H18N2O
Molar mass	218.300 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@]12CCN([C@@H]1N(C3=C2C=C(C=C3)O)C)C;
	InChI InChI=1S/C13H18N2O/c1-13-6-7-14(2)12(13)15(3)11-5-4-9(16)8-10(11)13/h4-5,8,12,16H,6-7H2,1-3H3/t12-,13+/m1/s1; Key:HKGWQUVGHPDEBZ-OLZOCXBDSA-N;
	(verify)

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 [62-44-2] (1) with dimethylsulfate gives N-methylphenetidine [3154-18-5] (2). Treatment with 2-bromopropanoyl bromide [563-76-8] gave 2-bromo-N-(4-ethoxyphenyl)-N-methylpropanamide [153880-70-7] (3). Treatment with aluminium trichloride resulted in 1,3-dimethyl-5-hydroxyoxindole [1010-68-0] (4). Alkylation with diethylsulfate gave 5-Ethoxy-1,3-dimethylindolin-2-one [131057-63-1] [131042-86-9] (5). Base catalyzed treatment with Chloroacetonitrile [107-14-2] gave 2-(5-ethoxy-1,3-dimethyl-2-oxoindol-3-yl)acetonitrile, PC15227456 (6). Catalytic hydrogenation of the nitrile group gave (7). Mono-methylation of the primary amine gave (8). Intramolecular reductive amination gave Eserethole [469-23-8] (9). Cleavage of the ethyl ether protecting group gave (-)-Eseroline [469-22-7] (10). Optional treatment with methylisocyanide (MIC) leads to physostigmine.

References

^ Fürst S, Friedmann T, Bartolini A, Bartolini R, Aiello-Malmberg P, Galli A, et al. (September 1982). "Direct evidence that eseroline possesses morphine-like effects". European Journal of Pharmacology. 83 (3–4): 233–41. doi:10.1016/0014-2999(82)90256-4. PMID 6293841.
^ Jhamandas K, Elliott J, Sutak M (March 1981). "Opiatelike actions of eseroline, an eserine derivative". Canadian Journal of Physiology and Pharmacology. 59 (3): 307–10. doi:10.1139/y81-048. PMID 7194726.
^ Galli A, Renzi G, Grazzini E, Bartolini R, Aiello-Malmberg P, Bartolini A (April 1982). "Reversible inhibition of acetylcholinesterase by eseroline, an opioid agonist structurally related to physostigmine (eserine) and morphine". Biochemical Pharmacology. 31 (7): 1233–8. doi:10.1016/0006-2952(82)90009-0. PMID 7092918.
^ Agresti A, Buffoni F, Kaufman JJ, Petrongolo C (November 1980). "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. PMID 7464812.
^ Galli A, Ranaudo E, Giannini L, Costagli C (November 1996). "Reversible inhibition of cholinesterases by opioids: possible pharmacological consequences". The Journal of Pharmacy and Pharmacology. 48 (11): 1164–8. doi:10.1111/j.2042-7158.1996.tb03914.x. PMID 8961166. S2CID 45395195.
^ Liu WF (April 1991). "Effect of eseroline on schedule-controlled behavior in the rat". Pharmacology, Biochemistry, and Behavior. 38 (4): 747–51. doi:10.1016/0091-3057(91)90236-U. PMID 1871191. S2CID 12857298.
^ Berkenbosch A, Rupreht J, DeGoede J, Olievier CN, Wolsink JG (February 1993). "Effects of eseroline on the ventilatory response to CO2". European Journal of Pharmacology. 232 (1): 21–8. doi:10.1016/0014-2999(93)90723-U. PMID 8458393.
^ Somani SM, Kutty RK, Krishna G (October 1990). "Eseroline, a metabolite of physostigmine, induces neuronal cell death". Toxicology and Applied Pharmacology. 106 (1): 28–37. doi:10.1016/0041-008X(90)90102-Z. PMID 2251681.
^ Kulkarni, Mukund G.; Dhondge, Attrimuni P.; Borhade, Ajit S.; Gaikwad, Dnyaneshwar D.; Chavhan, Sanjay W.; Shaikh, Yunnus B.; Ningdale, Vijay B.; Desai, Mayur P.; Birhade, Deekshaputra R.; Shinde, Mahadev P. (2009). "A novel and efficient total synthesis of (±)-physostigmine". Tetrahedron Letters. 50 (20): 2411–2413. doi:10.1016/j.tetlet.2009.03.012.
^ Thomas B. K. Lee & George S. K. Wong, WO1994027963 (Aventis Pharmaceuticals Inc).
^ Harley-Mason, J. et al, J. Chem. Soc., 1954, 3651.
^ Wijnberg, J.B.P.A. et al, Tetrahedron, 1978, 34, 2399.

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[1] Fürst S, Friedmann T, Bartolini A, Bartolini R, Aiello-Malmberg P, Galli A, et al. (September 1982). "Direct evidence that eseroline possesses morphine-like effects". European Journal of Pharmacology. 83 (3–4): 233–41. doi:10.1016/0014-2999(82)90256-4. PMID 6293841.

[2] Jhamandas K, Elliott J, Sutak M (March 1981). "Opiatelike actions of eseroline, an eserine derivative". Canadian Journal of Physiology and Pharmacology. 59 (3): 307–10. doi:10.1139/y81-048. PMID 7194726.

[3] Galli A, Renzi G, Grazzini E, Bartolini R, Aiello-Malmberg P, Bartolini A (April 1982). "Reversible inhibition of acetylcholinesterase by eseroline, an opioid agonist structurally related to physostigmine (eserine) and morphine". Biochemical Pharmacology. 31 (7): 1233–8. doi:10.1016/0006-2952(82)90009-0. PMID 7092918.

[4] Agresti A, Buffoni F, Kaufman JJ, Petrongolo C (November 1980). "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. PMID 7464812.

[5] Galli A, Ranaudo E, Giannini L, Costagli C (November 1996). "Reversible inhibition of cholinesterases by opioids: possible pharmacological consequences". The Journal of Pharmacy and Pharmacology. 48 (11): 1164–8. doi:10.1111/j.2042-7158.1996.tb03914.x. PMID 8961166. S2CID 45395195.

[6] Liu WF (April 1991). "Effect of eseroline on schedule-controlled behavior in the rat". Pharmacology, Biochemistry, and Behavior. 38 (4): 747–51. doi:10.1016/0091-3057(91)90236-U. PMID 1871191. S2CID 12857298.

[7] Berkenbosch A, Rupreht J, DeGoede J, Olievier CN, Wolsink JG (February 1993). "Effects of eseroline on the ventilatory response to CO2". European Journal of Pharmacology. 232 (1): 21–8. doi:10.1016/0014-2999(93)90723-U. PMID 8458393.

[8] Somani SM, Kutty RK, Krishna G (October 1990). "Eseroline, a metabolite of physostigmine, induces neuronal cell death". Toxicology and Applied Pharmacology. 106 (1): 28–37. doi:10.1016/0041-008X(90)90102-Z. PMID 2251681.

[9] Kulkarni, Mukund G.; Dhondge, Attrimuni P.; Borhade, Ajit S.; Gaikwad, Dnyaneshwar D.; Chavhan, Sanjay W.; Shaikh, Yunnus B.; Ningdale, Vijay B.; Desai, Mayur P.; Birhade, Deekshaputra R.; Shinde, Mahadev P. (2009). "A novel and efficient total synthesis of (±)-physostigmine". Tetrahedron Letters. 50 (20): 2411–2413. doi:10.1016/j.tetlet.2009.03.012.

[10] Thomas B. K. Lee & George S. K. Wong, WO1994027963 (Aventis Pharmaceuticals Inc).

[11] Harley-Mason, J. et al, J. Chem. Soc., 1954, 3651.

[12] Wijnberg, J.B.P.A. et al, Tetrahedron, 1978, 34, 2399.

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