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

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

Author information

1
Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice, Slovakia. Electronic address: gazova@saske.sk.
2
Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
3
Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
4
Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice, Slovakia.
5
Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
6
Institute of Physiology, Czech Academy of Science, Videnska 1083, 142 20 Prague, Czech Republic.
7
Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Sciences Center, TX, USA.

Abstract

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

PMID:
27865910
DOI:
10.1016/j.bbadis.2016.11.020
[Indexed for MEDLINE]
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