Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer's disease drugs.
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.
Weinreb
Orly
O
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, 31096, Israel.
Mandel
Silvia
S
Bar-Am
Orit
O
Yogev-Falach
Merav
M
Avramovich-Tirosh
Yael
Y
Amit
Tamar
T
Youdim
Moussa B H
MB
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000627:therapeutic use*; D007189:Indans / Q000737:chemistry / Q000627:therapeutic use*; D007502:Iron Chelating Agents / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000378:metabolism
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D006912:Hydroxyquinolines; D007189:Indans; D007502:Iron Chelating Agents; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C031967:rasagiline; D011493:Protein Kinase C