title: Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations.
abstract: Nantenine, as well as a number of flexible analogs, were evaluated for acetylcholinesterase (AChE) inhibitory activity in microplate spectrophotometric assays based on Ellman's method. It was found that the rigid aporphine core of nantenine is an important structural requirement for its anticholinesterase activity. Nantenine showed mixed inhibition kinetics in enzyme assays. Molecular docking experiments suggest that nantenine binds preferentially to the catalytic site of AChE but is also capable of interacting with the peripheral anionic site (PAS) of the enzyme, thus accounting for its mixed inhibition profile. The aporphine core of nantenine may thus be a useful template for the design of novel PAS or dual-site AChE inhibitors. Inhibiting the PAS is desirable for prevention of aggregation of the amyloid peptide Aβ, a major causative factor in the progression of Alzheimer's disease (AD).
authors.affiliation: City University of New York Hunter College, Department of Chemistry, New York, NY 10065, USA.
authors.forename: Stevan
authors.initials: S
authors.lastname: Pecic
authors.forename: Marie A
authors.initials: MA
authors.lastname: McAnuff
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Harding
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000544:Alzheimer Disease / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D001060:Aporphines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004593:Electrophorus; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D001060:Aporphines; D002800:Cholinesterase Inhibitors; C081279:aporphine; D000110:Acetylcholinesterase; C041615:nantenine