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

Biomolecules

Vladimir Finger¹  Marketa Benkova¹  Lukas Prchal¹  Tereza Kobrlova¹  Tomas Kucera²  Lenka Pulkrabkova²  Daniel Jun²  Jan Korabecny²  Martina Hrabinova²  Ondrej Soukup²  Jan Konecny²  Stepan Kortus³  Anna Misiachna³  Martin Horak³  Marharyta Kolcheva³  Marian Valko⁴ 

[1] Biomedical Research Centre, 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;Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic;Slovak University of Technology, Faculty of Chemical and Food Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia;

关键词: acetylcholinesterase;    Alzheimer’s disease;    butyrylcholinesterase;    fluorene;    in vitro;    in silico;   

DOI  :  10.3390/biom11010003

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown