Cited by 163Cholinesterase and Neurodegenerative DiseasesChemical synthesis and alkaloidsAlzheimer's disease research and treatments

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

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Simoni, Elena, Daniele, Simona, Bottegoni, Giovanni, Pizzirani, Daniela, Trincavelli, Maria L., Goldoni, Luca, Tarozzo, Glauco, Reggiani, Angelo +5 more·2012·Journal of Medicinal Chemistry

Abstract

Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).

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Crossref · 10.1021/jm3009458

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Authors
Simoni, E., Daniele, S., Bottegoni, G., Pizzirani, D., Trincavelli, M. L., Goldoni, L., Tarozzo, G., Reggiani, A., Martini, C., Piomelli, D., Melchiorre, C., Rosini, M., & Cavalli, A.
Affiliations
  • Italian Institute of Technology (IT)
  • University of Pisa (IT)
  • University of California, Irvine (US)
  • University of Bologna (IT)
Corresponding author
  • Rosini, Michela
  • Cavalli, Andrea
Venue
Journal of Medicinal Chemistry
Published
2012-10-17
Volume
55
Issue
22
Pages
9708-9721
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W1966242585
Cited by
163
References
48
Citations by year
2026: 10 · 2025: 11 · 2024: 14 · 2023: 6 · 2022: 17 · 2021: 8 · 2020: 15 · 2019: 20 · 2018: 8 · 2017: 15 · 2016: 15 · 2015: 9 · 2014: 11 · 2013: 4
FWCI
5.87
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical synthesis and alkaloids
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
galantamine, memantine, multi-target drugs, Alzheimer's disease, acetylcholinesterase inhibitors, NMDA receptor, NR2B subunit, NMDA-induced neurotoxicity, neuroprotection, hybrid molecules, spacers
MeSH terms
Acetylcholinesterase, Alzheimer Disease, Animals, Cerebral Cortex, Cholinesterase Inhibitors, Computer Simulation, Drug Combinations, Feasibility Studies, Galantamine, Humans, Male, Memantine, Neuroblastoma, Drug Design, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Neuroprotective Agents, Cell Proliferation, Rats

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