Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

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.

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

“…Combining compounds with different neuroprotective mechanisms might reduce secondary neuronal damage. Memantine mitigates glutamate excitotoxicity via NMDA receptor antagonism (Marotta et al 2020;Stojiljkovic et al 2019). Memantine alone fails to terminate seizure activity because of cholinergic overstimulation (Jackson et al 2019;Shih et al 1999).…”

“…In the moderate or severe stages of AD, the AChEI effect is supported by memantine. Together, they can synergistically and effectively tackle the AD pathological cascade (Marotta et al 2020;Tariot and Federoff 2003). This approach may also be beneficial for the pretreatment of highly toxic OPs.…”

Cholinesterase inhibitors and memantine for the treatment of Alzheimer and non-Alzheimer dementias

“…in patients already using ChEis), continuation of the ChEi is recommended, since combination of the agents is more effective on cognitive, ADL and BPSD symptoms than their isolated use 35 . Fixed combination formulation is also available, containing memantine and donepezil 1 and there are recently designed memantine-ChEi and memantine-antioxidant hybrid small molecules in experimental phase for multitarget approaches as well 36 . To minimize side effects, a slow titration dosing over 4 weeks is recommended to reach the target dose of 20 mg/day.…”

Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer’s Disease: Synthesis, Docking and Biological Evaluation

“…Apparently, the presence of antioxidant properties for the synthesized hydroxamic acids can be associated with the inclusion of adamantane, fenchane, and camphane fragments in the CAP group. The presence of antioxidant activity for a number of adamantane derivatives is known from the literature [27]. Thus, for the adamantane derivative memantine, the literature describes the ability to reduce oxidative damage in the cortex and hippocampus of the rat brain, two important brain regions involved in the formation of memory [39].…”

“…Adamantane, which can be found in petroleum and the monoterpene compounds camphane and fenchane themselves, has demonstrated promising pharmacological effects that are potentially useful for Alzheimer's disease (AD) treatment, such as antioxidant effects and neuroprotective properties; moreover, one of the few anti-Alzheimer drugs, memantine, has been derived on the basis of adamantane [27,28]. In addition, it has been shown that memantine-based hydroxamic acids are able to penetrate the blood-brain barrier [29].…”