RESUMEN
Drug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective antimicrobial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. In this work, we develop a multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells during transitions between separate environmental conditions. With this platform, we implement a dynamic single-cell screening for pheno-tuning compounds, which induce a phenotypic change and decrease cell-to-cell variation, aiming to undermine the entire bacterial population and make it more vulnerable to other drugs. We apply this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our lead compound impairs Mycobacterium tuberculosis via a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that harnessing phenotypic variation represents a successful approach to tackle pathogens that are increasingly difficult to treat.
Asunto(s)
Antituberculosos , Mycobacterium tuberculosis , Análisis de la Célula Individual , Tuberculosis , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Análisis de la Célula Individual/métodos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Humanos , Pruebas de Sensibilidad Microbiana , Microfluídica/métodos , Fenotipo , Descubrimiento de Drogas/métodos , Sinergismo FarmacológicoRESUMEN
The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer's disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug-drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design.
RESUMEN
The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer's disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.
Asunto(s)
Inhibidores de la Colinesterasa/química , Desarrollo de Medicamentos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Sitios de Unión , Técnicas de Química Sintética , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Humanos , Enlace de Hidrógeno , Ligandos , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 µM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (Ki = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Profármacos/farmacología , Receptores de Serotonina/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Electrophorus , Humanos , Locomoción/efectos de los fármacos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Relación Estructura-ActividadRESUMEN
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).
Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Donepezilo/síntesis química , Donepezilo/uso terapéutico , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/uso terapéutico , Donepezilo/química , Donepezilo/farmacología , Humanos , Modelos Moleculares , Conformación Molecular , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/uso terapéutico , EstereoisomerismoRESUMEN
Several phenanthrolinic analogs of quinolones have been synthesized and their antibacterial activity tested against Mycobacterium tuberculosis, other mycobacterial species and bacteria from other genera. Some of them show high activity (of the range observed for rifampicin) against M. tuberculosis replicating in vitro and in vivo (infected macrophages) conditions. These derivatives show the same activity with all or several M. tuberculosis complex bacterial mutants resistant to fluoroquinolones (FQ). This opens the way to the construction of new drugs for the treatment of FQ resistant bacterial infections, including tuberculosis. Several compounds showed also activity against Staphylococcus aureus and probably other species. These compounds do not show major toxicity. We conclude that the novel phenanthrolinic derivatives described here are potent hits for further developments of new antibiotics against bacterial infectious diseases including tuberculosis in particular those resistant to FQ.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Fenantrolinas/química , Quinolonas/química , Quinolonas/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Pruebas de Sensibilidad MicrobianaRESUMEN
INTRODUCTION: Numerous chemotypes have been described over time in order to generate potent and selective 5-HT4R ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years. AREAS COVERED: This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HT4R modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses. EXPERT OPINION: The therapeutic potential of 5-HT4R modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HT4R modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HT4R modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development.
Asunto(s)
Receptores de Serotonina 5-HT4/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Antagonistas del Receptor de Serotonina 5-HT4/farmacología , Animales , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/fisiopatología , Desarrollo de Medicamentos , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/fisiopatología , Humanos , Ligandos , Patentes como Asunto , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/efectos adversos , Antagonistas del Receptor de Serotonina 5-HT4/efectos adversosRESUMEN
A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.
Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Diseño de Fármacos , Isoxazoles/uso terapéutico , Receptores de Serotonina 5-HT4/metabolismo , Enfermedad de Alzheimer/patología , Sitios de Unión , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Donepezilo/química , Donepezilo/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/química , Isoxazoles/farmacología , Modelos Moleculares , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND AND PURPOSE: We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD). EXPERIMENTAL APPROACH: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-ß 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-ß peptides on neuronal survival and neurite formation determined in vitro. KEY RESULTS: 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-ß peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses. CONCLUSIONS AND IMPLICATIONS: 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.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Compuestos de Anilina , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Piperidinas , RatasRESUMEN
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
Asunto(s)
Acetilcolinesterasa/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Profármacos/farmacología , Acetilcolinesterasa/química , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/patología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Carbamatos/química , Inhibidores de la Colinesterasa/química , Humanos , Ligandos , Profármacos/química , Receptores de Serotonina 5-HT4/genéticaRESUMEN
Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aß protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells. Such MTDL were obtained by linking on a central piperidine two scaffolds of interest: a typical aminochlorobenzophenone present in numerous 5-HT4R agonists, and diverse antioxidant chemotypes. Interestingly, the most active compound 9g possesses a Ki of 12.7â¯nM towards 5-HT4R and an antioxidant activity in vitro and in cellulo.
Asunto(s)
Antioxidantes/farmacología , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/metabolismo , Células COS , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Estructura Molecular , Picratos/antagonistas & inhibidores , Picratos/metabolismo , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/síntesis química , Agonistas del Receptor de Serotonina 5-HT4/química , Relación Estructura-ActividadRESUMEN
This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer's disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan-1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.
RESUMEN
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-HT4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the σ1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.
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Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/síntesis química , Indoles/farmacología , Agonistas del Receptor de Serotonina 5-HT4/síntesis química , Acetilcolinesterasa/efectos de los fármacos , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Inhibidores de la Colinesterasa/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Indoles/síntesis química , Ligandos , Piperidinas/química , Piperidinas/farmacología , Receptores de Serotonina 5-HT4/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT4/farmacología , TorpedoRESUMEN
Herein we describe the drug design steps developed to increase the radical scavenging and ß-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Depuradores de Radicales Libres/farmacología , Alcaloides de Pirrolicidina/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/síntesis química , Antagonistas de Receptores Adrenérgicos alfa 2/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Humanos , Modelos Moleculares , Estructura Molecular , Agregado de Proteínas/efectos de los fármacos , Alcaloides de Pirrolicidina/síntesis química , Alcaloides de Pirrolicidina/química , Relación Estructura-ActividadRESUMEN
This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid ß (ßA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate ßA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Antioxidantes/farmacología , Compuestos de Bencilo/farmacología , Agregado de Proteínas/efectos de los fármacos , Pirroles/farmacología , Enfermedad de Alzheimer/metabolismo , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bencilo/síntesis química , Compuestos de Bencilo/química , Proliferación Celular , Relación Dosis-Respuesta a Droga , Humanos , Células KB , Modelos Moleculares , Estructura Molecular , Unión Proteica/efectos de los fármacos , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Despite its implication in several physiological and pathological processes the serotonin subtype-4 receptor (5-HT4R) has seen limited effort for the development of radiolabeling agent especially concerning single photon emission computed tomography (SPECT). Bearing an ester function, the available ligands are rapidly susceptible to hydrolysis which limits their use in vivo. In this study the synthesis of iodinated benzamide and ketone analogs were described. Their affinity for the 5-HT4R and their lipophilicity were evaluated and the most promising derivatives were evaluated ex vivo for their binding to the receptor and for their ability to displace the reference ligand [(125)I]-SB207710.
Asunto(s)
Benzamidas/síntesis química , Cetonas/síntesis química , Receptores de Serotonina 5-HT4/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Benzamidas/química , Técnicas de Química Sintética , Humanos , Radioisótopos de Yodo , Cetonas/química , Trazadores Radiactivos , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Piperidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT4/química , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Inhibidores de la Colinesterasa/química , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Cobayas , Humanos , Ligandos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Endogámicos , Terapia Molecular Dirigida , Piperidinas/administración & dosificación , Piperidinas/química , Receptores de Serotonina 5-HT4/metabolismo , Relación Estructura-Actividad , Pruebas de Toxicidad AgudaRESUMEN
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-ß 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.