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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

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

Author(s): Agnieszka Jankowska, Anna Wesolowska*, Maciej Pawlowski and Grazyna Chlon-Rzepa*

Volume 25, Issue 17, 2018

Page: [2045 - 2067] Pages: 23

DOI: 10.2174/0929867324666170529122802

Price: $65


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.

Keywords: Alzheimer's disease, multi-target-directed ligands, serotonin, serotonin receptor ligands, serotonin reuptake inhibitors, neurotransmitter systems, second messenger system.

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