From Anti-Parkinson's Drug Rasagiline to Novel Multitarget Iron Chelators with Acetylcholinesterase and Monoamine Oxidase Inhibitory and Neuroprotective Properties for Alzheimer's Disease
Affiliations: [a] Department of Medicinal Chemistry, Intra-Cellular Therapies Inc., New York, NY, USA | [b] Eve Topf Center of Excellence for Neurodegenerative Diseases and Department of Pharmacology, Technion-Rappaport Family Faculty of Medicine Haifa, Israel | [c] Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel | [d] Department of Biology, Yonsei World Central University, Seoul, South Korea
Correspondence:
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Correspondence to: Dr. Silvia A. Mandel, Eve Topf Centers for Neurodegenerative Diseases, Department of Pharmacology, Technion – Faculty of Medicine, Haifa, Israel. Tel.: +972 4 8295 290; Fax: +972 4 8513 145; E-mail: mandel@tx.technion.ac.il.
Abstract: Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.
