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  Y
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 (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.

Eseroline synthesis:

References

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. Bibcode:1990ToxAP.106...28S. doi:10.1016/0041-008X(90)90102-Z. PMID   2251681.
9. Kulkarni MG, Dhondge AP, Borhade AS, Gaikwad DD, Chavhan SW, Shaikh YB, et al. (2009). "A novel and efficient total synthesis of (±)-physostigmine". Tetrahedron Letters. 50 (20): 2411–2413. doi:10.1016/j.tetlet.2009.03.012.
10. Harley-Mason J, Jackson AH (1954). "Hydroxytryptamines. Part II. A new synthesis of physostigmine". Journal of the Chemical Society (Resumed): 3651–3654. doi:10.1039/JR9540003651.
11. Wijberg JB, Speckamp WN (January 1978). "New total synthesis of dl-physostigmine (dl-eserine) via regioselective NaBH4-reduction of imides". Tetrahedron. 34 (15): 2399–2404. doi:10.1016/0040-4020(78)89058-9.