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International audience; 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.

International audience; 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.

International audience; 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.

BACKGROUND AND PURPOSE: We recently identified donecopride as a pleiotropic compound able to inhibit acetylcholinesterase and to activate serotonin subtype 4 receptor. The purpose of the present article is to establish its potential therapeutic interest against Alzheimer's disease (AD). EXPERIMENTAL APPROACH: The present work used both in cellulo and in vivo models of AD. KEY RESULTS: In the present study, we show that, in vivo under chronic administration, donecopride displays potent anti-amnesic properties in two different animal models of Alzheimer's disease (AD) (transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides). Donecopride preserved learning capacities, including working and long-term spatial memories, which were evaluated with various behavioral tests (novel object recognition, Y-maze, Morris water maze). These behavioral observations found molecular correlation with the interactions of donecopride related to the two main types of molecular damage in AD. Indeed, a decrease in amyloid aggregation was observed in the brain of the treated transgenic mice, as well as a reduction in tau hyperphosphorylation in rat primary cultures of hippocampal neurons. At the cellular level, donecopride exerted neuroprotective effects toward neurons and the neurite network, as well as neurotrophic benefits, expressed as the formation of new synapses. CONCLUSIONS & IMPLICATIONS: Pleiotropic donecopride acts like a Swiss army knife, displaying sustainable symptomatic therapeutic effects and potential disease-modifying roles against AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.

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.

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.

Alzheimer&rsquo, 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 &micro, M) and (h)MAO-B (IC50 = 6.4 &micro, M).

International audience; 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-HT4R agonists, and diverse antioxidant chemotypes. Interestingly, the most active compound 9g possesses a Ki of 12.7 nM towards 5-HT4R and an antioxidant activity in vitro and in cellulo.

Alzheimer&rsquo, 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.

International audience; Herein we describe the drug design steps developed to increase the radical scavenging and β-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

International audience; 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 [125I]-SB207710.

International audience; 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.

Study background: We previously revealed that the arrestin 2 was differentially involved in the regulation of the human delta opioid receptor (hDOR) by peptidic and alkaloid agonists. In the present study, we examined whether i) hDOR regulation by two related alkaloid agonists (etorphine and morphine) involved the same arrestins ii) similar arrestin-dependent mechanisms occur upon short- and long-term agonist exposure. Methods: The human neuroblastoma SK-N-BE cells, endogenously expressing hDOR, were transfected with wild-type or mutant arrestins. Using shRNA, we also generated a clonal cell line depleted in arrestin 2, the only arrestin isoform expressed in this cell line. Cells were then exposed or not to either morphine ou etorphine for short- (1 h) or long-term (18 h), then receptor desensitization was examined on the cAMP pathway and internalization was visualized by confocal microscopy. Results: In arrestin 2-depleted cells, we observed a strong reduction of desensitization after 18 h of morphine exposure but not with etorphine. Over-expression of wild-type or mutant arrestins produced an opposite modulation of receptor desensitization induced by morphine and etorphine both upon short- and long-term exposure. Confocal fluorescence microscopy experiments did not reveal any strong impact on receptor internalization when different arrestins were over-expressed. Conclusion: Our results showed that i) two related opioid alkaloid agonists produce hDOR desensitization by different mechanisms ii) the involvement of arrestins in hDOR desensitization depends on the duration of agonist exposure.