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Multi-Target-Directed Ligands Affecting Serotonergic Neurotransmission for Alzheimer's Disease Therapy: Advances in Chemical and Biological Research

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Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive impairments and chronic inflammation that affects over 30 million people all over the world. Most of the Alzheimer's patients also suffer from psychosis, aggression, agitation, depression, anxiety, and many other behavioral and psychological symptoms of dementia. Unfortunately, the currently available anti-AD drugs provide modest symptomatic relief, and they do not reverse the neurodegeneration. Therefore, the average life expectancy after diagnosis is between six and ten years. Research data suggest that multi-target-directed ligands (MTDLs) give an opportunity to prevent, halt, or reverse the progression of AD, and reduce the symptoms of the disease. The aim of this review is to update the most recent reports on the development of MTDLs affecting serotonergic neurotransmission as potential drugs for both symptomatic and disease-modifying therapy of AD. Multifunctional modulators of serotonergic system exerted procognitive, antipsychotic, antidepressant, and/or anxiolytic properties in preclinical studies. Some of them revealed their potential as modulators of tau phosphorylation or amyloid beta aggregation with neuroprotective, anti-inflammatory, and/or antioxidant properties. Among them, lumateperone - an inhibitor of serotonin transporter with a high affinity for serotonergic and dopaminergic receptors is currently being tested in clinical trials in patients with dementia, bipolar depression, or schizophrenia. The high therapeutic potential of MTDLs as anti-AD drugs seems to be the result of their involvement in multiple neurotransmitter systems and intracellular signaling pathways.
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Keywords: Alzheimer's disease; multi-target-directed ligands; neurotransmitter systems; second messenger system; serotonin; serotonin receptor ligands; serotonin reuptake inhibitors

Document Type: Review Article

Publication date: May 1, 2018

This article was made available online on September 12, 2017 as a Fast Track article with title: "Multi-Target-Directed Ligands Affecting Serotonergic Neurotransmission for Alzheimer’s Disease Therapy: Advances in Chemical and Biological Research".

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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