Cargando…

Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists

Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficac...

Descripción completa

Detalles Bibliográficos
Autores principales: Konecny, Jan, Misiachna, Anna, Hrabinova, Martina, Pulkrabkova, Lenka, Benkova, Marketa, Prchal, Lukas, Kucera, Tomas, Kobrlova, Tereza, Finger, Vladimir, Kolcheva, Marharyta, Kortus, Stepan, Jun, Daniel, Valko, Marian, Horak, Martin, Soukup, Ondrej, Korabecny, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822176/
https://www.ncbi.nlm.nih.gov/pubmed/33375115
http://dx.doi.org/10.3390/biom11010003
_version_ 1783639572764164096
author Konecny, Jan
Misiachna, Anna
Hrabinova, Martina
Pulkrabkova, Lenka
Benkova, Marketa
Prchal, Lukas
Kucera, Tomas
Kobrlova, Tereza
Finger, Vladimir
Kolcheva, Marharyta
Kortus, Stepan
Jun, Daniel
Valko, Marian
Horak, Martin
Soukup, Ondrej
Korabecny, Jan
author_facet Konecny, Jan
Misiachna, Anna
Hrabinova, Martina
Pulkrabkova, Lenka
Benkova, Marketa
Prchal, Lukas
Kucera, Tomas
Kobrlova, Tereza
Finger, Vladimir
Kolcheva, Marharyta
Kortus, Stepan
Jun, Daniel
Valko, Marian
Horak, Martin
Soukup, Ondrej
Korabecny, Jan
author_sort Konecny, Jan
collection PubMed
description Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
format Online
Article
Text
id pubmed-7822176
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-78221762021-01-23 Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists Konecny, Jan Misiachna, Anna Hrabinova, Martina Pulkrabkova, Lenka Benkova, Marketa Prchal, Lukas Kucera, Tomas Kobrlova, Tereza Finger, Vladimir Kolcheva, Marharyta Kortus, Stepan Jun, Daniel Valko, Marian Horak, Martin Soukup, Ondrej Korabecny, Jan Biomolecules Article Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE. MDPI 2020-12-22 /pmc/articles/PMC7822176/ /pubmed/33375115 http://dx.doi.org/10.3390/biom11010003 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Konecny, Jan
Misiachna, Anna
Hrabinova, Martina
Pulkrabkova, Lenka
Benkova, Marketa
Prchal, Lukas
Kucera, Tomas
Kobrlova, Tereza
Finger, Vladimir
Kolcheva, Marharyta
Kortus, Stepan
Jun, Daniel
Valko, Marian
Horak, Martin
Soukup, Ondrej
Korabecny, Jan
Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
title Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
title_full Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
title_fullStr Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
title_full_unstemmed Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
title_short Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
title_sort pursuing the complexity of alzheimer’s disease: discovery of fluoren-9-amines as selective butyrylcholinesterase inhibitors and n-methyl-d-aspartate receptor antagonists
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822176/
https://www.ncbi.nlm.nih.gov/pubmed/33375115
http://dx.doi.org/10.3390/biom11010003
work_keys_str_mv AT konecnyjan pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT misiachnaanna pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT hrabinovamartina pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT pulkrabkovalenka pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT benkovamarketa pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT prchallukas pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT kuceratomas pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT kobrlovatereza pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT fingervladimir pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT kolchevamarharyta pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT kortusstepan pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT jundaniel pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT valkomarian pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT horakmartin pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT soukupondrej pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists
AT korabecnyjan pursuingthecomplexityofalzheimersdiseasediscoveryoffluoren9aminesasselectivebutyrylcholinesteraseinhibitorsandnmethyldaspartatereceptorantagonists