Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is characterized
as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment
based on acetylcholinesterase (AChE) inhibitors and N–methyl-D-aspartate receptors (NMDAR) antagonist is
effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature
of the disease. In this context, the so-called “multi-targeting" approach has been established.
Objectives: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for
the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity
mediated by the NMDAR receptors.
Methods: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine.
Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective
efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and
predicted the ability to cross the blood-brain barrier.
Results: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent
hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the
AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results 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 MTDL design strategy was indicated 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.
Conclusion: We 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.