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).

New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine

“…The preparation of N 6 analogs was achieved by N -alklyation of secondary (±)-amine 17 (see ref 4) under reductive amination conditions (Figure 4)…”

A Route to Azafluoranthene Natural Products Through Direct Arylation

“…[12] Our own work on aporphines have explored the synthesis and bioactivity of nantenine derivatives as serotonin 5-HT 2A and α 1A adrenergic receptor antagonists, [13] cytotoxic agents [14] and acetylcholinesterase inhibitors. [15] …”

C4 phenyl aporphines with selective h5-HT2B receptor affinity

“…1–6 Moreover, in the central nervous system (CNS), aporphines have been investigated as acetylcholinesterase inhibitors 7,8 and as ligands for serotonin, adrenergic and dopamine receptors. 9–14 …”