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]

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
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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:^[9][10][11]