Document Detail

Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease.
MedLine Citation:
PMID:  23033965     Owner:  NLM     Status:  MEDLINE    
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).
Elena Simoni; Simona Daniele; Giovanni Bottegoni; Daniela Pizzirani; Maria L Trincavelli; Luca Goldoni; Glauco Tarozzo; Angelo Reggiani; Claudia Martini; Daniele Piomelli; Carlo Melchiorre; Michela Rosini; Andrea Cavalli
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-17
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  55     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-26     Completed Date:  2013-02-05     Revised Date:  2013-02-13    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9708-21     Citation Subset:  IM    
Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
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MeSH Terms
Acetylcholinesterase / chemistry
Alzheimer Disease / prevention & control
Cell Proliferation / drug effects
Cerebral Cortex / drug effects,  metabolism
Cholinesterase Inhibitors / pharmacology*
Computer Simulation
Drug Combinations
Drug Design
Feasibility Studies
Galantamine / pharmacology*
Memantine / pharmacology*
Neuroblastoma / drug therapy*
Neuroprotective Agents / pharmacology*
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / metabolism
Reg. No./Substance:
0/Cholinesterase Inhibitors; 0/Drug Combinations; 0/NR2B NMDA receptor; 0/Neuroprotective Agents; 0/Receptors, N-Methyl-D-Aspartate; 19982-08-2/Memantine; 357-70-0/Galantamine; EC

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