Syntheses and anticholinesterase activities of (3aS)-N1, N8-bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine, their antipodal isomers, and other potential metabolites of phenserine.
Hydrolysis of the carbamate side chains in phenserine [(-)1] and physostigmine [(-)2] yields the metabolite (-)-eseroline (3), and the red dye rubreserine (4) on air oxidation of the former compound. Both compounds lacked anticholinesterase activity in concentrations up to 30 mM, which would be unachievable in vivo. A second group of potential metabolites of 1 and 2 are the N1,N8-bisnorcarbamates (-)9 and (-)10, prepared from (3aS)-N8-benzylnoresermethole (-)12 by the carbinolamine route. These entirely novel compounds proved to be highly potent inhibitors of acetylcholinesterase [(-)9] and of acetyl- and butyrylcholinesterase (AChE and BChE) [(-)10], respectively. To elucidate further the structure/anticholinesterase activity relationship of the described compounds, the antipodal isomers (3aR)-N1,N8-bisnorcarbamates (+)9 and (+)10 were likewise synthesized from (3aR)-N8-benzylnoresermethole (+)12 and assessed. The compounds possessed moderate but less potent anticholinesterase activity, with the same selectivity as their 3aS enantiomers. Finally, the anticholinesterase activities of intermediates N1, N8-bisnorbenzylcarbamates (-)18, (-) 19, (+)18, and (+)19, also novel compounds, were additionally measured. The 3aS enantiomers proved to be potent and selective inhibitors of BChE, particularly (-)19, whereas the antipodal isomers lacked activity.
Yu
Q
Q
School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599-7361, USA.
Greig
N H
NH
Holloway
H W
HW
Brossi
A
A
D000110:Acetylcholinesterase / Q000097:blood; D002091:Butyrylcholinesterase / Q000097:blood; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D048448:Phenylcarbamates; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007211:Indoles; C112869:N(1),N(8)-bisnorphenserine; C112870:N(1),N(8)-bisnorphysostigmine; D048448:Phenylcarbamates; C027950:rubreserine; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C022594:eseroline; C092280:phenserine