title: Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment.
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.
authors.affiliation: Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice, Slovakia. Electronic address: gazova@saske.sk.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Gazova
authors.affiliation: 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.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: 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.
authors.forename: Vendula
authors.initials: V
authors.lastname: Sepsova
authors.affiliation: Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice, Slovakia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Siposova
authors.affiliation: Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Drtinova
authors.affiliation: 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.
authors.forename: Petr
authors.initials: P
authors.lastname: Jost
authors.affiliation: 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.
authors.forename: Katarina
authors.initials: K
authors.lastname: Spilovska
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: 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.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Nepovimova
authors.affiliation: Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice, Slovakia.
authors.forename: Diana
authors.initials: D
authors.lastname: Fedunova
authors.affiliation: Institute of Physiology, Czech Academy of Science, Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Horak
authors.affiliation: Institute of Physiology, Czech Academy of Science, Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Kaniakova
authors.affiliation: Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Sciences Center, TX, USA.
authors.forename: Ze-Jun
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M Health Sciences Center, TX, USA.
authors.forename: Ayman K
authors.initials: AK
authors.lastname: Hamouda
authors.affiliation: 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.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000547:Amantadine / Q000031:analogs & derivatives / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002802:Cholinesterases / Q000378:metabolism; D003412:Cricetulus; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014981:Xenopus
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D043643:Receptor, Muscarinic M1; D011950:Receptors, Cholinergic; D016194:Receptors, N-Methyl-D-Aspartate; D013619:Tacrine; C016222:7-methoxytacrine; D000547:Amantadine; D002802:Cholinesterases; D053829:Amyloid Precursor Protein Secretases
keywords: Aggregation; Alzheimer's disease; Amyloid; Aβ peptide; Muscarinic/nicotinic acetylcholine receptor antagonist; N-Methyl-d-aspartate receptor antagonist; β-Secretase inhibitor