Abstract
In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Aniline Compounds / administration & dosage
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Animals
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / pharmacology*
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Computer Simulation
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Crystallography, X-Ray
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Drug Design
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Drug Evaluation, Preclinical / methods
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Guinea Pigs
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Humans
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Ligands
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Male
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Memory, Short-Term / drug effects
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Molecular Targeted Therapy
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Piperidines / administration & dosage
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Piperidines / chemistry
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Piperidines / pharmacology*
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Receptors, Serotonin, 5-HT4 / metabolism
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Serotonin 5-HT4 Receptor Agonists / chemistry*
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Serotonin 5-HT4 Receptor Agonists / pharmacology*
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Structure-Activity Relationship
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Toxicity Tests, Acute
Substances
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Aniline Compounds
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Cholinesterase Inhibitors
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Ligands
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Piperidines
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Serotonin 5-HT4 Receptor Agonists
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donecopride
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Receptors, Serotonin, 5-HT4