Abstract
Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative condition that slowly destroys nerve cells, leading to a progressive cognitive decline
In able this the approach has applied by differentdifferent researchpathways groups to obtain hybrid review, we present selected examples of small molecules designed single entity the to hit simultaneously different pathways implicated in AD
Even if they effectively bind to the P2X7R, they did not show an improved activity for N-methyl-D-aspartate receptor (NMDAR) compared to memantine
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative condition that slowly destroys nerve cells, leading to a progressive cognitive decline. N-methyl-D-aspartate (NMDA) receptors (NMDAR) are ionotropic glutamate receptors primarily involved in synaptic plasticity underlying learning and memory They are prime actors of excitotoxic damage occurring during chronic neurodegenerative injuries [1]. Memantine is an uncompetitive NMDAR antagonist approved to treat moderate-severe AD patients It acts as an open-channel blocker with a relatively rapid off-rate from the channel [4]. Ligands (MTDLs), i.e., single molecules acting that could target glutamatergic and excitotoxicity-related mechanisms, triggering a on different targets simultaneously, emerging at Ligands a rapid pace as a valuable opportunity to restore synergistic response [15]. In the search for a diseaseis viewed as a privileged NMDAR-directed structure, and represents the driving motif in the modifying drug forofAD, the MTDL approach has been applied research groups obtain design of a variety multifunctional compounds. Action, such as antioxidant and anti-aggregating activity or AChE and monoaminoxidase inhibition
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