td-5108 and Alzheimer-Disease

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Cognition; Humans; Parasympathetic Nervous System; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT

Topics: Alzheimer Disease; Cognition Disorders; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Neuroprotective Agents; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship

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 Aβ 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-HT

Topics: Alzheimer Disease; Animals; Antioxidants; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorocebus aethiops; COS Cells; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Ligands; Molecular Structure; Picrates; Reactive Oxygen Species; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship

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

It is widely assumed that the upcoming therapeutics for Alzheimer's disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task.. For spontaneous alternation behavior, combination of 1 mg/kg galantamine and 0.5 mg/kg RS-67333 fully reversed the deficit. In the passive avoidance task, no sub-efficacious doses could be found in the retention paradigm, but a beneficial effect of the association has been demonstrated in the acquisition paradigm.. Mnesic effects of galantamine can be thus potentiated by activation of 5-HT4R. Such a combination treatment might (1) strengthen symptomatic relief, (2) attenuate adverse effects given the lower doses of each compound required, and (3) afford a disease-modifying effect given the known action of 5-HT4R on amyloidogenesis cascade.

Topics: Allosteric Regulation; Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Galantamine; Male; Memory Disorders; Mice; Nicotinic Antagonists; Piperidines; Receptors, Nicotinic; Receptors, Serotonin, 5-HT4; Scopolamine; Serotonin 5-HT4 Receptor Agonists

Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Behavior, Animal; Disease Models, Animal; Encephalitis; Entorhinal Cortex; Learning; Male; Memory; Mice, Transgenic; Neuroglia; Piperidines; Plaque, Amyloid; Serotonin 5-HT4 Receptor Agonists

5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Chemistry Techniques, Synthetic; Drug Design; Guinea Pigs; HEK293 Cells; Humans; Ligands; Male; Mice; Molecular Targeted Therapy; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

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

Alzheimer's disease (AD) is the most common form of dementia affecting 35 million individuals worldwide. Current AD treatments provide only brief symptomatic relief. It is therefore urgent to replace this symptomatic approach with a curative one. Increasing serotonin signaling as well as developing molecules that enhance serotonin concentration in the synaptic cleft have been debated as possible therapeutic strategies to slow the progression of AD. In this Viewpoint, we discuss exciting new insights regarding the modulation of serotonin signaling for AD prevention and therapy.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Clinical Trials as Topic; Humans; Nootropic Agents; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

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

In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT(4)Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT(4) receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT(4) receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing.

Topics: ADAM Proteins; ADAM10 Protein; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Benzofurans; Cerebral Cortex; Cyclic AMP; HEK293 Cells; Humans; Membrane Proteins; Neuroprotective Agents; Receptors, G-Protein-Coupled; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; CHO Cells; Cognition Disorders; Cricetinae; Cricetulus; Cyclic AMP; Dogs; Drug Partial Agonism; Haplorhini; HEK293 Cells; Humans; In Vitro Techniques; Indoles; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver; Permeability; Piperidines; Protein Isoforms; Pyrans; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Stereoisomerism; Structure-Activity Relationship

Serotonin 5-HT(4) receptor (5-HT(4)R) agonists are of particular interest for the treatment of Alzheimer's disease because of their ability to ameliorate cognitive deficits and to modulate production of amyloid beta-protein (Abeta). However, despite the range of 5-HT(4)R agonists synthesized to date, potent and selective 5-HT(4)R agonists are still lacking. In the present study, two libraries of molecules based on the scaffold of ML10302, a highly specific and partial 5-HT(4)R agonist, were efficiently prepared by parallel supported synthesis and their binding affinities and agonist activities evaluated. Furthermore, we showed that, in vivo, the two best candidates exhibited neuroprotective activity by increasing the level of the soluble form of the amyloid precursor protein (sAPPalpha) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit Abeta fibril formation in vitro.

Topics: Alzheimer Disease; Aminobenzoates; Amyloid; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Biopolymers; Cell Line, Tumor; Cerebral Cortex; Cyclic AMP; Drug Design; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; para-Aminobenzoates; Peptide Fragments; Piperidines; Radioligand Assay; Rats; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship

Activation of 5-HT4 receptors has been shown to improve memory processes in preclinical cognition models, suggesting potential utility of 5-HT4 agonists for the symptomatic treatment of Alzheimer's disease (AD). Recent studies have shown that 5-HT4 agonists also increase the secretion of the non-amyloidogenic soluble amyloid precursor protein-alpha (sAPPalpha). In the present study, we demonstrated that a selective 5-HT4 partial agonist, RS67333, inhibited the generation of beta-amyloid peptide (Abeta) in primary cortical cultures of Tg2576 transgenic mice expressing human APP(K670N/M671L). Furthermore, treatments with RS67333 selectively increased the survival of transgenic neurons in a dose-dependent manner, which was inhibited by 5-HT4 antagonists. These and previous data collectively suggest that the 5-HT4 receptor may be an effective therapeutic target for AD, providing both symptomatic improvements and neuroprotection.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Cell Survival; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Male; Mice; Mice, Transgenic; Nerve Degeneration; Neurons; Neuroprotective Agents; Peptide Fragments; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Synaptic Transmission; Treatment Outcome