Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease
Open accessAbstract
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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ARN14140 (30) showed the best compromise between pharmacological and pharmacokinetic properties among the series.
“Among the series, shorter tethered ARN14140 (30) showed the best compromise between pharmacological and pharmacokinetic properties.”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [113]
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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
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- 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
- green
- escholarship.org
- 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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