Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment

Biochim Biophys Acta Mol Basis Dis. 2017 Feb;1863(2):607-619. doi: 10.1016/j.bbadis.2016.11.020. Epub 2016 Nov 16.


Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with β-secretase (BACE1) activity, Aβ peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N-methyl-d-aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively Aβ peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.

Keywords: Aggregation; Alzheimer's disease; Amyloid; Aβ peptide; Muscarinic/nicotinic acetylcholine receptor antagonist; N-Methyl-d-aspartate receptor antagonist; β-Secretase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amantadine / analogs & derivatives
  • Amantadine / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • CHO Cells
  • Cholinesterases / metabolism
  • Cricetulus
  • Dimerization
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Targeted Therapy
  • Receptor, Muscarinic M1 / antagonists & inhibitors
  • Receptor, Muscarinic M1 / metabolism
  • Receptors, Cholinergic / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Tacrine / analogs & derivatives*
  • Tacrine / chemistry
  • Tacrine / pharmacology
  • Xenopus


  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Receptor, Muscarinic M1
  • Receptors, Cholinergic
  • Receptors, N-Methyl-D-Aspartate
  • Tacrine
  • 7-methoxytacrine
  • Amantadine
  • Cholinesterases
  • Amyloid Precursor Protein Secretases