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

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, IC 50 = 0.28 nM).

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…Interestingly, 1 (memagal in Figure 2) carrying a hexamethylene spacer resulted in one of the most promising compounds of the series. In agreement with molecular modelling studies, six methylenes constituted the optimal distance to allow 1 to efficiently contact the AChE CAS and PAS, resulting in a nanomolar AChE inhibitor (IC 50 = 1.16 nM) [25].…”

“…Interestingly, 1 (memagal in Figure 2) carrying a hexamethylene spacer resulted in one of the most promising compounds of the series. In agreement with molecular modelling studies, six methylenes constituted the optimal distance to allow 1 to efficiently contact the AChE CAS and PAS, resulting in a nanomolar AChE inhibitor (IC50 = 1.16 nM) [25]. Therefore, novel dual-target compounds were developed by connecting the two drugs through variable-length polymethylene spacers and heteroatom linkers [25] (Figure 2).…”

“…Several review articles describing the status and advances of this class of MTDLs have been recently published, to whom the reader is directed for a more comprehensive discussion [19][20][21][22][23][24]. By following a conjugation approach, in 2012, some of us developed a new series of hybrid compounds that integrated the pharmacological activities of two drugs marketed for AD, which are the acetylcholinesterase inhibitor (AChEI) galantamine and the N-methyl-D-aspartate receptor (NMDAR) antagonist memantine [25] (Figure 2). The design aim was to combine in the same molecule the neuroprotective effect of NMDAR antagonism with the symptomatic relief provided by cholinergic neurotransmission through acetylcholinesterase (AChE) inhibition.…”

“…On this basis, galantamine and memantine, working together on the same excitotoxic cascade, could provide a synergistic neuroprotective effect. Therefore, novel dual-target compounds were developed by connecting the two drugs through variable-length polymethylene spacers and heteroatom linkers [25] (Figure 2).…”

p53 Functional Inhibitors Behaving Like Pifithrin-β Counteract the Alzheimer Peptide Non-β-amyloid Component Effects in Human SH-SY5Y Cells

“…In light of these findings, previous studies have been devoted to identifying druglike compounds endowed with pharmacological activities better than those exhibited by pifithrin-α and pifithrin-β. 21−23 The primary aim of this study was to evaluate the involvement of p53 signaling in human neuroblastoma SH-SY5Y cells, 13 a cell line suitable for AD models, 24 treated with NAC as a toxic insult. Subsequently, to set up an in vitro predictive test for the assessment of potential anti-AD agents that can interfere with p53 function, the NAC effects were evaluated in the presence of pifithrin-β.…”