donecopride and Alzheimer-Disease

Complex diseases (e.g., Alzheimer's disease) or infectious diseases are usually caused by complicated and varied factors, including environmental and genetic factors. Multi-target (polypharmacology) drugs have been suggested and have emerged as powerful and promising alternative paradigms in modern medicinal chemistry for the development of versatile chemotherapeutic agents to solve these medical challenges. The multifunctional agents capable of modulating multiple biological targets simultaneously display great advantages of higher efficacy, improved safety profile, and simpler administration compared to single-targeted agents. Therefore, multifunctional agents would certainly open novel avenues to rationally design the next generation of more effective but less toxic therapeutic agents. Herein, the authors review the recent progress made in the discovery and design processes of selective multi-targeted agents, especially the successful application of multi-target drugs for the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Drug Discovery; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in elderly people. Considering the multifactorial nature of AD, the concept of multi-target-directed ligands (MTDLs) has recently emerged as a new strategy for designing therapeutic agents on AD. MTDLs are confirmed to simultaneously affect diverse targets which contribute to etiology of AD. As the most potent approved drug, donepezil affects various events of AD, like inhibiting cholinesterases activities, anti-Aβ aggregation, anti-oxidative stress et al. Modifications of donepezil or hybrids with pharmacophores of donepezil in recent five years are summarized in this article. On the basis of case studies, our concerns and opinions about development of donepezil derivatives, designing of MTDLs, and perspectives for AD treatments are discussed in final part.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Drug Discovery; Humans; Indans; Ligands; Molecular Docking Simulation; Oxidative Stress; Piperidines

A novel series of 2-(2- oxoethyl)pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that compound 10q showed the best inhibitory activity against AChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Drug Design; Humans; Molecular Docking Simulation; Pyrimidines; Structure-Activity Relationship

We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT. We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-β peptides on neuronal survival and neurite formation determined in vitro.. In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.. Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease-modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Brain; Disease Models, Animal; Maze Learning; Mice; Mice, Transgenic; Piperidines; Rats

Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT

Topics: Acetylcholinesterase; Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Crystallography, X-Ray; Drug Design; Humans; Indoles; Ligands; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Torpedo

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.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Computer Simulation; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Guinea Pigs; Humans; Ligands; Male; Memory, Short-Term; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Targeted Therapy; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship; Toxicity Tests, Acute

RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Chlorocebus aethiops; Cholinesterase Inhibitors; Cognition; COS Cells; Cyclosporine; Drug Design; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Kinetics; Ligands; Mice; Permeability; Piperidines; Receptors, Serotonin, 5-HT4; Rhodamine 123; Serotonin 5-HT4 Receptor Agonists; Solubility; Task Performance and Analysis