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 neuroprotective/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.