molecules Review Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease Giambattista Marotta , Filippo Basagni , Michela Rosini and Anna Minarini * Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; [email protected] (G.M.); fi[email protected] (F.B.); [email protected] (M.R.) * Correspondence: [email protected] Academic Editors: Maria Novella Romanelli and Silvia Dei Received: 10 July 2020; Accepted: 1 September 2020; Published: 2 September 2020 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. Keywords: memantine; Alzheimer’s disease; multi target directed ligand; hybrid structures 1. Introduction Alzheimer’s disease (AD) is a chronic neurodegenerative condition that slowly destroys nerve cells, leading to a progressive cognitive decline. As for major chronic diseases, a pluralism of causative features is thought to be implicated, resulting in complex networks of perturbation. The mechanistic understanding of synaptic damage might offer a valuable key for developing future therapeutic strategies to tackle AD progression. In this context, excitotoxicity is emerging as a pivotal event. Caused by excessive or prolonged glutamate exposure, this pathological condition alters neurons to death. N-methyl-D-aspartate (NMDA) receptors (NMDAR) are ionotropic glutamate receptors primarily involved in synaptic plasticity underlying learning and memory. However, they are also prime actors of excitotoxic damage occurring during chronic neurodegenerative injuries [1]. Increasing consensus indicates that functional properties of NMDAR are governed by their localization, with synaptic NMDAR (sNMDAR) contributing to cell plasticity and neurotrophic processes, while extrasynaptic NMDAR (eNMDAR) triggering apoptotic signalling pathways [2]. This effect accounts for the difficulties encountered in the design of safe and effective cures acting on NMDARs, and contemporary suggests that a selective targeting of the eNMDARs represents a promising approach to treat neurodegenerative conditions [3]. 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]. Molecules 2020, 25, 4005; doi:10.3390/molecules25174005 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 20 Memantine is an uncompetitive NMDAR antagonist approved to treat moderate-severe AD Molecules 2020, 25, 4005 2 of 20 patients. It acts as an open-channel blocker with a relatively rapid off-rate from the channel [4]. Due to these peculiar kinetics, memantine mainly enters the channel in conditions of excessive and Dueprolonged to these glutamate peculiar kinetics,exposure, memantine preferentially mainly acting enters on theextrasynaptic/tonically channel in conditions-activated of excessive NMDAR and prolongedover synaptic/phasically glutamate exposure,-activated preferentially NMDAR [5,6]. acting This on peculiar extrasynaptic profile,/tonically-activated which allows memantine NMDAR to overcontrast synaptic excitotoxicity/phasically-activated while preservi NMDARng glutamatergic [5,6]. This synaptic peculiar functioning, profile, which possibly allows accounts memantine for the to contrastclinical tolerability excitotoxicity of the while drug preserving [7]. Unfortunately, glutamatergic however, synaptic memantine functioning, offers only possibly palliative accounts benefits for theto patients. clinical tolerability Possibly, ofthe the explanation drug [7]. Unfortunately,for this issue however,might be memantine the complex off ersneurotransm only palliativeitters benefitsdysfunction to patients. characterizing Possibly, AD, the which explanation suggests for the this modulation issue might of be a thesingle complex neurotransmitter neurotransmitters system dysfunctionto be inadequate characterizing to face the AD, disease. which Increasing suggests the evidence modulation indicates of a singlea mutual neurotransmitter feedback connection system tobetween be inadequate the glutamatergic to face the and disease. the cholinergic Increasing systems, evidence which indicates both apossess mutual strong feedback implications connection in betweencognitive the functions glutamatergic [8]. Furthermore, and the cholinergic the failure systems, of calcium which homeostatic both possess balance strong deriving implications from inNMDAR cognitive overactivation functions [8 ].as Furthermore, well as metal the dyshomeostasis failure of calcium (Fe, homeostaticZn, Cu) [9,10] balance orchestrate derivings several from NMDARpathologic overactivation features, including as well oxidative as metal damage dyshomeostasis [11,12], neuroinflammation (Fe, Zn, Cu) [9,10 and] orchestrates protein misfolding several pathologicand aggregation features, [13,14] including, all contributing oxidative damage to the [11 neurotoxicity,12], neuroinflammation mediated by and excitotoxic protein misfolding damage. andIndeed, aggregation the presence [13,14 of], neuritic all contributing plaques toconstituted the neurotoxicity mainly by mediated insoluble by Aβ excitotoxic-peptide damage.(Aβ) in the Indeed, brain theparenchyma, presence ofis one neuritic of the plaques hallmarks constituted required for mainly AD diagnosis. by insoluble Aβ-peptide (Aβ) in the brain parenchyma,On this basis, is one research of the hallmarks efforts have required recently for focused AD diagnosis. on the identification of therapeutic tools that couldOn target this basis,glutamatergic research ehyperactivationfforts have recently and focused excitotoxicity on the-related identification mechani ofsms, therapeutic triggering tools a thatsynergistic could target response glutamatergic [15]. Thus, hyperactivationMulti Target Directed and excitotoxicity-related Ligands (MTDLs), i.e. mechanisms,, single molecules triggering acting a synergisticon different response targets simultaneously, [15]. Thus, Multi are Target emerging Directed at Ligandsa rapid pace (MTDLs), as a valuable i.e., single opportunity molecules actingto restore on dithefferent complex targets interplay simultaneously, among aremulti emergingple NMDAR at a rapid-mediated pace as aalterations valuable opportunity[16,17]. In tothis restore context, the complexmemantine interplay is viewed among as multiplea privileged NMDAR-mediated NMDAR-directed alterations structure, [16,17 and]. In therefore this context,, represents memantine the isdriving viewed motif as a privilegedin the design NMDAR-directed of a variety of structure, multifunctional and therefore, compounds. represents In the the search driving for motif a disease in the- designmodifyin of ag varietydrug for of AD, multifunctional the MTDL approach compounds. has been In the applied search by for different a disease-modifying research groups drug to for obtain AD, thehybrid MTDL compounds approach hasable been to hit applied simultaneously by different different research pathways groups to obtainimplicated hybrid in compoundsAD [18]. In ablethis toreview, hit simultaneously we present selected different examples pathways of small implicated molecules in AD designed [18]. In by this mergi review,ng in we a presentsingle entity selected the examplesamantadine of smallcore moleculesof memantine designed with bythe merging chemical in features a single entityof known the amantadine neuroprotectants core of memantineperforming withthrough the chemicaldifferent featuresmechanism of known of action, neuroprotectants such as antioxidant performing and anti through-aggregating different activity mechanism or AChE of action,and monoaminoxidase such as antioxidant inhibition and anti-aggregating (Figure 1). activity or AChE and monoaminoxidase inhibition (Figure1). Figure 1. Conjugation strategies exploiting memantine’s NMDAR antagonism to tackle AD. Molecules 2020, 25, 4005 3 of 20 2. Memantine and Cholinesterase Inhibitor Hybrids To date, only two classes of drugs are licensed for the treatment of AD: AChEIs for mild to-moderate disease and memantine for moderate and severe disease. AChEIs prevent cholinesterase enzymes (ChEs) from degrading acetylcholine (ACh), in order to increase the synaptic concentration and the duration of action of the neurotransmitter [19]. Among the various