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Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer's Disease.

A novel molecule 2 formed by combining 6-chlorotacrine (6-Cl-THA) and memantine proved to be a promising multipotent hybrid capable of blocking the action of acetylcholinesterase (AChE) as well as N-methyl-D-aspartate receptors (NMDARs). The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6 Cl THA twofold. Our recently reported results have pointed out that apart from its anticholinesterase activity tacrine is able to block NMDARs. However, the mechanism of such inhibitory effect is different from that of memantine. According to results obtained in vitro with NMDARs, it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood brain barrier via passive diffusion. Finally, the multi-target-directed ligand (MTDL) design strategy was vindicated by in vivo results which showed that the novel 6-Cl-THA memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. Thus, we have shown that the combination of two parent substances varying in their mechanism of block of the NMDAR leads to a substance with a potent neuroprotective effect in vivo, surpassing that of the parent memantine. We can conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.