{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T22:00:32Z","timestamp":1787868032577,"version":"build-2784847793"},"reference-count":81,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN 2017 (2017MT3993_007)"],"award-info":[{"award-number":["PRIN 2017 (2017MT3993_007)"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u2019s 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 A\u03b2-aggregation inhibitors.<\/jats:p>","DOI":"10.3390\/molecules25174005","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T11:07:14Z","timestamp":1599044834000},"page":"4005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Memantine Derivatives as Multitarget Agents in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5846-3532","authenticated-orcid":false,"given":"Giambattista","family":"Marotta","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0710-4251","authenticated-orcid":false,"given":"Filippo","family":"Basagni","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Rosini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4905-0944","authenticated-orcid":false,"given":"Anna","family":"Minarini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.neuron.2014.03.030","article-title":"Extrasynaptic NMDA receptor involvement in central nervous system disorders","volume":"82","author":"Parsons","year":"2014","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4258","DOI":"10.1096\/fj.08-107268","article-title":"Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors","volume":"22","author":"Gouix","year":"2008","journal-title":"FASEB J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.3233\/JAD-170672","article-title":"Memantine for the Treatment of Dementia: A Review on its Current and Future Applications","volume":"62","author":"Folch","year":"2018","journal-title":"J. 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