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 cellbased assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDAinduced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC50 = 0.28 nM).

Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease / 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.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 55:(2012), pp. 9708-9721. [10.1021/jm3009458]

Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease.

MELCHIORRE, CARLO;ROSINI, MICHELA;CAVALLI, ANDREA
2012

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 cellbased assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDAinduced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC50 = 0.28 nM).
2012
Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease / 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.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 55:(2012), pp. 9708-9721. [10.1021/jm3009458]
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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/132625
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