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  • Novel multi-target-directed ligands for Alzheimer's disease : combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation
    Więckowska, Anna ...
    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.
    Source: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 124, 29 Nov. 2016, str. 63-81)
    Type of material - article, component part ; adult, serious
    Publish date - 2016
    Language - english
    COBISS.SI-ID - 4144753

    Link(s):

    http://www.sciencedirect.com/science/article/pii/S0223523416306596

    Dostop preko računalnikov UL


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