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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9708-9721
• 全文大小：409K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

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, IC₅₀ = 0.28 nM).