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

0474014 - FGÚ 2018 RIV NL eng J - Journal Article
Gažová, Z. - Soukup, O. - Šepsová, V. - Šipošová, K. - Drtinová, L. - Jošt, P. - Spilovská, K. - Korábečný, J. - Nepovímová, E. - Fedunová, D. - Horák, Martin - Kaniaková, Martina - Wang, Z. J. - Hamouda, A. K. - Kuča, K.
Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment.
Biochimica Et Biophysica Acta-Molecular Basis of Disease. Roč. 1863, č. 2 (2017), s. 607-619. ISSN 0925-4439. E-ISSN 1879-260X
R&D Projects: GA ČR(CZ) GA16-08554S
Institutional support: RVO:67985823
Keywords : amyloid * aggregation * muscarinic/nicotinic acetylcholine receptor antagonist * N-Methyl-d-aspartate receptor antagonist * Alzheimer's disease * A beta peptide * beta-secretase inhibitor
OECD category: Neurosciences (including psychophysiology
Impact factor: 5.108, year: 2017

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 beta-secretase (BACE1) activity, A beta 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 A beta 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.
Permanent Link: http://hdl.handle.net/11104/0271109