The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
29533874
DOI
10.1016/j.ejmech.2018.02.083
PII: S0223-5234(18)30226-5
Knihovny.cz E-zdroje
- Klíčová slova
- 7-Methoxytacrine, Acetylcholinesterase, Acetylcholinesterase inhibitor, Alzheimer's disease, BQCA, Butyrylcholinesterase, Multi-target directed ligands, Positive allosteric modulator of muscarinic receptor, Tacrine,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- buněčné linie MeSH
- butyrylcholinesterasa metabolismus MeSH
- chinoliny chemie farmakologie MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- Cricetulus MeSH
- lidé MeSH
- molekulární struktura MeSH
- takrin chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid MeSH Prohlížeč
- acetylcholinesterasa MeSH
- butyrylcholinesterasa MeSH
- chinoliny MeSH
- cholinesterasové inhibitory MeSH
- takrin MeSH
Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 μM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.
Biomedical Research Centre University Hospital Sokolska 581 500 05 Hradec Kralove Czech Republic
National Institute of Mental Health Topolova 748 250 67 Klecany Czech Republic
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