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Eur J Med Chem. 2016 Nov 29;124:63-81. doi: 10.1016/j.ejmech.2016.08.016. Epub 2016 Aug 11.

Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation.

Author information

1
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland. Electronic address: anna.wieckowska@uj.edu.pl.
2
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
3
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
4
Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
5
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
6
Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, 9 Medyczna Str., 30-688, Kraków, Poland.
7
Institute of Psychiatry and Neurology, 9 Sobieskiego Str., 02-957, Warsaw, Poland.
8
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia.

Abstract

As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT6 receptor (Kb = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC50hAChE = 12 nM, IC50hBuChE = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.

KEYWORDS:

5-HT(6) receptor antagonists; Acetylcholinesterase inhibitors; Alzheimer's disease; Butyrylcholinesterase inhibitors; Multi-target-directed ligands

PMID:
27560283
DOI:
10.1016/j.ejmech.2016.08.016
[Indexed for MEDLINE]

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