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Neurotherapeutics logoLink to Neurotherapeutics
. 2009 Jan;6(1):163–174. doi: 10.1016/j.nurt.2008.10.030

Multifunctional neuroprotective derivatives of rasagiline as anti-alzheimer’s disease drugs

Orly Weinreb 1,2, Silvia Mandel 1,2, Orit Bar-Am 1,2, Merav Yogev-Falach 1,2, Yael Avramovich-Tirosh 1,2, Tamar Amit 1,2, Moussa B H Youdim 1,2,✉
PMCID: PMC5084264  PMID: 19110207

Summary

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drugs, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuro-protective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine. A second derivative of rasagiline, M-30 was developed by amalgamating the propargyl moiety of rasagiline into the skeleton of our novel brain permeable neuroprotective iron chelator, VK-28. Preclinical experiments showed that both compounds have anti-Alzheimer’s disease activities and thus, the clinical development is oriented toward treatment of this type of dementia. This review discusses the multimodal effects of two rasagiline-containing hybrid molecules, namely ladostigil and M-30, concerning their neuroprotective molecular mechanisms in vivo and in vitro, including regulation of amyloid precursor protein processing, activation of protein kinase C, and mitogen-activated protein kinase signaling pathways, inhibition of cell death markers and upregulation of neurotrophic factors. Altogether, these scientific findings make these multifunctional compounds potentially valuable drugs for the treatment of Alzheimer’s disease.

Key Words: Alzheimer’s disease, amyloid precursor protein, multifunctional drugs, propargyl moiety, cholinesterase inhibitor, iron chelator

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