ArticleProceedings of the National Academy of Sciences of the United States of America2014
Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 117 citations in OpenAlex.
- Prokinetic drugs that stimulate 5-HTNaunyn-Schmiedeberg's archives of pharmacology · 2026Review
- 5-HT4 Receptor Ligand RS67333 Modulates Striatal Acetylcholine and Dopamine Release via the Inhibition of Acetylcholinesterase.ACS chemical neuroscience · 2026Article
- Shared molecular mechanisms in aging and neurodegenerative diseases: from mechanistic insights to therapeutic strategies.Frontiers in human neuroscience · 2026Review
- Multi-Target Drug Design in Alzheimer's Disease Treatment: Emerging Technologies, Advantages, Challenges, and Limitations.Pharmacology research & perspectives · 2025Review
- Pathway-based network medicine identifies novel natural products for Alzheimer's disease.Alzheimer's research & therapy · 2025Article
- Evidence from a mouse model supports repurposing an anti-asthmatic drug, bambuterol, against Alzheimer's disease by administration through an intranasal route.Communications biology · 2025Article
- Studies on the mechanisms of action of MR33317.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Multitarget-Directed Ligands Hitting Serotonin Receptors: A Medicinal Chemistry Survey.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Development of Pleiotropic TrkB and 5-HTMolecules (Basel, Switzerland) · 2024Article
- Superiority of the Triple-Acting 5-HTJournal of medicinal chemistry · 2023Article
- Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer's Disease.Pharmaceutics · 2023Review
- Anticholinesterase and Serotoninergic Evaluation of Benzimidazole-Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease.Pharmaceutics · 2023Article
- Cardiac Roles of Serotonin (5-HT) and 5-HT-Receptors in Health and Disease.International journal of molecular sciences · 2023Review
- Current Pharmacotherapy and Multi-Target Approaches for Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-Pharmaceuticals (Basel, Switzerland) · 2022Article
- Memory Disorders Related to Hippocampal Function: The Interest of 5-HTInternational journal of molecular sciences · 2021Review
- Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer's Disease Treatment.Pharmaceutics · 2021Article
- Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HTJournal of medicinal chemistry · 2021Article
- Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer's Disease Treatment through Rigidification Strategy.Molecules (Basel, Switzerland) · 2021Article
- A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration.Frontiers in pharmacology · 2021Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.