Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

Abstract

Background: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. Methods: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C₄-C₅ chains and 5 N-alkylated C₄-C₈ side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. Results: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. Conclusion: The N-alkylated derivative of 7-MEOTA bearing from C₄ side chains appears to be the most promising compound and should be evaluated in future in vivo research.

Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy

“…All receptor structures were prepared by the DockPrep function of UCSF Chimera (version 1.4) and converted to pdbqt-files by AutodockTools (v. 1.5.6) [ 67 , 68 ]. Flexible residues selection was based on previous experience ( h AChE) or spherical region around the binding cavity [ 69 , 70 , 71 , 72 , 73 , 74 , 75 ].…”